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Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

  • Ruben G. G. Leenders
    Ruben G. G. Leenders
    Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
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    Orcidhttps://orcid.org/0000-0001-6140-5405
  • , 
  • Shoshy Alam Brinch
    Shoshy Alam Brinch
    Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
    Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway
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  • , 
  • Sven T. Sowa
    Sven T. Sowa
    Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
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  • , 
  • Enya Amundsen-Isaksen
    Enya Amundsen-Isaksen
    Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
    Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway
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  • , 
  • Albert Galera-Prat
    Albert Galera-Prat
    Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
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  • , 
  • Sudarshan Murthy
    Sudarshan Murthy
    Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
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  • , 
  • Sjoerd Aertssen
    Sjoerd Aertssen
    Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
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  • , 
  • Johannes N. Smits
    Johannes N. Smits
    Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
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  • , 
  • Piotr Nieczypor
    Piotr Nieczypor
    Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
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  • , 
  • Eddy Damen
    Eddy Damen
    Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
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  • Anita Wegert
    Anita Wegert
    Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
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  • , 
  • Marc Nazaré
    Marc Nazaré
    Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany
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    Orcidhttps://orcid.org/0000-0002-1602-2330
  • , 
  • Lari Lehtiö
    Lari Lehtiö
    Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
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    Orcidhttps://orcid.org/0000-0001-7250-832X
  • , 
  • Jo Waaler
    Jo Waaler
    Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
    Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway
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    Orcidhttps://orcid.org/0000-0002-8501-6225
  • , and 
  • Stefan Krauss*
    Stefan Krauss
    Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway
    Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway
    *Email: [email protected]. Tel: +47 97610063.
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Cite this: J. Med. Chem. 2021, 64, 24, 17936–17949
Publication Date (Web):December 8, 2021
https://doi.org/10.1021/acs.jmedchem.1c01264

Copyright © 2021 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Tankyrase 1 and 2 (TNKS1/2) catalyze post-translational modification by poly-ADP-ribosylation of a plethora of target proteins. In this function, TNKS1/2 also impact the WNT/β-catenin and Hippo signaling pathways that are involved in numerous human disease conditions including cancer. Targeting TNKS1/2 with small-molecule inhibitors shows promising potential to modulate the involved pathways, thereby potentiating disease intervention. Based on our 1,2,4-triazole-based lead compound 1 (OM-1700), further structure–activity relationship analyses of East-, South- and West-single-point alterations and hybrids identified compound 24 (OM-153). Compound 24 showed picomolar IC50 inhibition in a cellular (HEK293) WNT/β-catenin signaling reporter assay, no off-target liabilities, overall favorable absorption, distribution, metabolism, and excretion (ADME) properties, and an improved pharmacokinetic profile in mice. Moreover, treatment with compound 24 induced dose-dependent biomarker engagement and reduced cell growth in the colon cancer cell line COLO 320DM.

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Introduction

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Tankyrase 1 and tankyrase 2 (TNKS1/2) are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that regulate the turnover of specific target proteins through covalently linking the cellular redox metabolite NAD+ to target proteins in a process called poly-ADP-ribosylation (PARylation). The PAR chain produced in this post-translational modification is subsequently recognized by the E3 ubiquitin ligase ring finger protein 146 (RNF146) leading to poly-ubiquitination of the PARylated target proteins followed by proteasomal degradation. (1−4) Independent of their catalytic activity, TNKS1/2 also provides scaffolding functions that are important in the formation of protein complexes. (5−8) TNKS1/2 PARylate a plethora of target proteins including peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α), telomeric repeat binding factor 1 (TRF1), phosphatase and tensin homologue (PTEN), AMP-activated protein kinase (AMPK), SRY-box transcription factor 9 (SOX9), and SH3 domain binding protein 2 (SH3BP2). (3,9−15) In particular, TNKS1/2 regulate the turnover of AXIN1, AXIN2 (AXIN1/2) and of angiomotin (AMOT) proteins at the crossroad of the elementary wingless-type mammary tumor virus integration site (WNT)/β-catenin and Hippo signaling pathways, respectively. (3,14,16,17) Hence, controlling the catalytic activity of tankyrase by pharmacological intervention provides an attractive tool for reducing WNT/β-catenin and Hippo signaling. (18,19)
Multiple potent TNKS1/2 inhibiting small molecules, including bicyclic lactams, compounds based on heteroalicyclic amide scaffolds, tricyclic fused ring systems and 1,2,4-triazole scaffolds, have been identified. These compounds block the catalytic domain of TNKS1/2, either by binding with high selectivity to the adenosine binding pocket (which differs from other members of the PARP family) or by binding to the more conserved nicotinamide pocket. The latter binding mode results in a lower selectivity across the PARP family. Other compounds target both pockets in the catalytic domain. (16,20−37) Inhibitors based on the 1,2,4-triazole scaffold such as JW74, (38) G007-LK, (21) OD336, (28) and OM-1700 (1) (39) target the adenosine binding pocket of the TNKS1/2 catalytic domain with high selectivity and are therefore able to display selectivity over other members of the PARP family.
Despite the significant progress in developing TNKS1/2 inhibitors, there is currently no viable TNKS1/2 specific inhibitor in clinical practice for any disease indication. Concerns that have hampered clinical trials of TNKS1/2 inhibitors include earlier reports indicating intestinal toxicity (40,41) and bone loss in mouse models, (13) although other studies show a beneficial effect of tankyrase inhibition on fracture healing. (42) Nevertheless, mice that have been treated for an extended time with a moderate dose of a tankyrase inhibitor have not shown visible adverse effects. (43) Ongoing studies suggest that it is possible to overcome a potential biotarget toxicity and recently the tankyrase inhibitors E7449 (a dual inhibitor of PARP1/2 and TNKS1/2) and STP1002 have entered clinical trials with dose escalation studies in patients with advanced solid tumors. (44,45) This clearly illustrates the potential of TNKS1/2 inhibitors and justifies the development of drugs directed toward TNKS1/2 inhibition with high potency and an optimized pharmacokinetic (PK) profile.
Here, we further optimize compounds based on the 1,2,4-triazole series as landmark compounds (21,28,38,39) and we present compounds reaching picomolar IC50 values in a cellular WNT/β-catenin signaling reporter assay, while also showing optimized absorption, distribution, metabolism, excretion (ADME), and pharmacokinetic (PK) properties.

Results and Discussion

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Compound Design Strategy

Starting from the previously described lead compound 1 (Figure 1) (39) and having developed synthetic methodologies for preparing compound iterations in a modular fashion (see Supporting Experimentals for the general scheme of synthesis), we aimed at further improving the potency of tankyrase inhibition and optimizing ADME and pharmacokinetic properties of 1. Optimization was motivated by the highly potent compounds discovered during the development of 1 (e.g., compounds 16, 21, and 27 as numbered in our preceding paper, (39) see Chart S-1). In addition to this, the pharmacokinetic properties of 1, primarily its half-life and exposure, necessitated further improvements.

Figure 1

Figure 1. Lead compound 1 (OM-1700) and main modifications.

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In the process of making next-generation derivatives based on these previous compounds, (39) we revisited South-, East-, and West-single-point mutations and hybrids thereof. From these structures, we selected six compounds based on their cellular activity and on the diversity of their molecular architecture. The properties of these six shortlisted compounds were evaluated in mouse peroral pharmacokinetic studies and compared with that of compound 1. The best compound of this set was selected and further evaluated with respect to early ADME properties, off-target effects, binding affinity in the catalytic pocket of the TNKS2 protein, as well as inhibition of WNT/β-catenin signaling and proliferation in the colon cancer cell line COLO 320DM. The results from these experiments culminated in the identification of a new 1,2,4-triazole based lead tankyrase inhibitor.

Structure–Activity Relationship (SAR) Investigation and Biological Evaluation

To further explore the SAR of the West- and South-regions of 1, single-point modifications departing from 1 were synthesized (Table 1). From these compounds, we concluded that a gain in potency in our in vitro TNKS2 assay and cell-based WNT/β-catenin signaling assay cannot be attained with compounds possessing the East 2-pyridyl group while changing South/West groups, and we therefore focused on compounds with annulated aromatic heterocycles such as naphthyridines and quinoxalines (46) (Table 2). Such variations enabled picomolar potencies as these moieties are able to form a significantly more efficient π–π-stacking interaction with His1048 and an additional hydrophobic interaction with Phe1035 as evidenced by the obtained co-crystal structures. (39)
Table 1. West Variations of 1 (OM-1700)a
a

The IC50 values of the compounds of this work were determined with both the TNKS2 biochemical assay (quadruplicates used for each concentration tested, 95% confidence intervals are given in parentheses) and the cellular (HEK293) WNT/β-catenin signaling reporter assay (triplicates used for each concentration tested, T/F-tests were performed for the IC50 curve fitting; all p > 0.95).

Table 2. East Naphthyridines and Quinoxalinesa
a

The IC50 values of the compounds of this work were determined with both the TNKS2 biochemical assay (quadruplicates used for each concentration tested, 95% confidence intervals are given in parentheses) and the cellular (HEK293) WNT/β-catenin signaling reporter assay (triplicates used for each concentration tested, T/F-tests were performed for the IC50 curve fitting; all p > 0.95). * indicates a shortlisted compound. # averages of multiple independent measurements; standard error of the means (SEMs) are shown in Table 5.

First, we explored a series based on the East-side 1,5-naphthyridine, either with or without a 3-fluoro substituent (Table 2). Since compound 15a was impaired by a high metabolic instability in mouse microsomes, we aimed at making the structure metabolically more stable by increasing the polarity with the introduction of a South-pyridyl-substitution and compounds 16–18 (Table 2) were prepared. In general, more polar compounds are expected to show greater metabolic stability. Compounds with such a South-pyridyl, however, proved to be less potent in the cellular WNT/β-catenin signaling reporter assay compared to 15a and only compound 18b with an IC50 value of 6 nM was selected for further characterization (Table 2). To improve potency of compounds 16–18 as earlier observed, a bicyclo[1.1.1]pentane core as an alternative to the cyclobutane influenced activity favorably (see, e.g., compound 19 as numbered in our preceding paper (39)). Unfortunately, here, compounds built on this bicyclo[1.1.1]pentane core lacked picomolar cellular activity when combined with a South-pyridyl moiety (compounds 19–21, Table 2) and these South-pyridyl structures were abandoned. Furthermore, a South-methyl thiophene group was introduced as a phenyl bio-isostere (47) (compounds 22 and 23, Table 2), resulting in potent inhibitors of which compound 22a was selected for further evaluation.
Finally, the introduction of an East quinoxaline moiety instead of the naphthyridine group (compound 24) again led to picomolar cellular activity (IC50 = 0.63 nM), and we prepared further variations based on a quinoxaline core to interrogate this part of the pharmacophore. Variations of lead 24 by four fluorine- and methyl-substituted quinoxalines showed similar inhibitory activity (compounds 25–28, Table 3) but by varying the West-moiety, highly efficacious inhibitors could be obtained with the quinoxaline East-group. Three of these compounds were selected for further profiling (compounds 30b, 31a, and 31b). This resulted in a short list of six inhibitors with relatively high structural diversity (Figure 2).

Figure 2

Figure 2. Short list of six compounds and 1 including their respective biochemical TNKS2 and cellular (HEK293) WNT/β-catenin signaling reporter assays IC50 values in nM. clog P and tPSA (in Å2) as calculated by DataWarrior v5.5.0. Moieties in color were different from 1.

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Table 3. East Quinoxaline Variationsa
a

The IC50 values of the compounds of this work were determined with both the TNKS2 biochemical assay (quadruplicates used for each concentration tested, 95% confidence intervals are given in parentheses) and the cellular (HEK293) WNT/β-catenin signaling reporter assay (triplicates used for each concentration tested, T/F-tests were performed for the IC50 curve fitting; all p > 0.95). * indicates shortlisted compound. # averages of multiple independent measurements; SEMs are shown in Table 5.

Next, the set of six shortlisted compounds (Figure 2) was subjected to mouse peroral pharmacokinetic (PK) analyses and compared with 1 (Table 4). Here, compounds 22a and 18b displayed a decreased exposure (area under the curve, AUC) while compound 31a showed an AUC similar to 1. In contrast, compound 30b showed a high AUC, however, with a small volume of distribution (0.33 L/kg), and consequently, none of these compounds were selected for further evaluation.
Table 4. Mouse PO PK 5 mg/kg and Kinetic Solubility Data of 1 and the Six Shortlisted Compounds
compoundt1/2 (h)tmax (h)Cmax (ng/mL)AUC 0 → t (ng/mL·h)AUC 0 → ∞ (ng/mL·h)MRT 0 → ∞ (h)Vd (L/kg)CL (L/h/kg)solubility (μM)
1 (OM-1700) (39)0.670.253203238423880.692.032.09>80
18b1.000.252853193221.5622.415.6>80
22a1.170.257795435471.3915.59.1450
24 (OM-153)1.500.51967494550382.392.150.9931
30b0.690.5651215 08315 1051.930.330.33>80
31a0.760.252770340134041.241.611.47>80
31b0.590.255796531353161.470.800.9413
Further, compounds 31b and 24 showed improved pharmacokinetic properties compared to 1 (Table 4). The AUCs for 31b and 24 were similar and about twice as high compared to the AUC for 1. The peak value (Cmax) of exposure of 24 was approximately 3 times lower compared to the peak value for compound 31b. In addition, 24 showed a more favorable volume of distribution and solubility compared to these data for compound 31b. Compared to 1, compound 24 possesses an AUC about twice as high and a peak value of about 60% of that of 1 resulting in a higher exposure with a lower peak level. In addition to this, efficacy in the cellular WNT/β-catenin signaling reporter assay was approximately 30 times higher while the clearance of 24 was about half of that of 1.
In summary, based on the overall improved mouse PK profile and the enhanced potency in the cellular WNT/β-catenin signaling reporter assay, compound 24 was designated as the best derivative.
Subsequently, compound 24 was further characterized and compared to benchmark structure 1 with respect to early ADME properties and off-target effects. Tested ADME parameters such as kinetic solubility, Caco-2 permeability and efflux, microsomal stabilities, mouse plasma stability, and mouse plasma protein binding were found to be in line with 1, while solubility was somewhat lower although in an acceptable range (Table 5).
Table 5. Profiling of Compound 24
parameter1 (OM-1700)24 (OM-153)
efficacy  
TNKS1 (IC50, nM (pIC50 ± SEM))a127 (6.90 ± 0.05)13 (7.90 ± 0.054)
TNKS2 (IC50, nM (pIC50 ± SEM))a14 (7.85 ± 0.04)2.0 (8.71 ± 0.069)
HEK293 reporter assay (IC50, nM (pIC50 ± SEM))19 (7.75 ± 0.067)0.63 (9.22 ± 0.037)
COLO 320DM/RKO cells (GI50, nM)650/>10 00010/>10 000
ADME  
kinetic solubility PBS pH = 7 (μM)>8031
Caco-2 A–B: Papp (10–6 cm/s)39.540.5
Caco-2 efflux ratio0.610.64
microsomal stability human/mouse/dog CLint (μL/min/mg protein)<5/27/nd18/22/3.8
mouse plasma stability t1/2 (min)>120>120
mouse PPB (%)93.9298.58
off-target  
PARPsb PARP1/2/3/4/10/12/14/15 (IC50, μM)>10>10
hERG inhibition (IC50, μM)>25>25
Ames testnongenotoxicnongenotoxic
CYP3A4 inhibition (IC50, μM)>25>25
CYP induction (human PXR)ndnonactivatorbc
Cerep Safety panel 44 targets@10 μM (inhibition)clean, (A2A, 53%)clean, (all <50%)
mouse pharmacokinetics  
PO PK mouse t1/2 (h)0.671.5
PO PK mouse Cmax (ng/mL)32021967
PO PK mouse CL (L/h/kg)2.090.99
PO PK mouse Vd (L/kg)2.032.15
PO PK mouse AUC 0 → t (ng/mL)23844945
calculated propertiesd  
MW (g/mol)458.5509.6
clog P3.13.4
tPSA95108
a

See Figure 1, Supporting Information.

b

See Table 1, Supporting Information.

c

Highest concentration, 100 μM.

d

Calculated by DataWarrior v5.5.0.

Next, we solved a co-crystal structure of TNKS2-24 demonstrating that 24 binds to the NAD+ cleft of the catalytic domain in a similar manner to the previously reported analogue 1 (39) (Figure 3). The observed electron density is clear for the compound except for an apparently mobile ethoxy group extending toward the nicotinamide site. The previously identified hydrogen bonds of the scaffold (39) were once more observed between 24 and the Tyr1060 and Asp1045 backbones, as well as with a water molecule. The quinoxaline moiety is forming π–π stacking interactions with both His1048 and Phe1035 providing improved binding affinity compared with that of 1.

Figure 3

Figure 3. Co-crystal structure of TNKS2 with 24 (PDB 7O6X). The protein is shown in blue, and 24 in green. The dashed lines in black represent hydrogen bonds, and the red spheres represent water molecules. The σA weighted 2Fo – Fc electron density maps around the ligands are contoured at 1.8σ.

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Finally, to complete the analysis of compound 24, COLO 320DM cells, likely of neuroendocrinal origin, (48) were treated with various doses of 24 to evaluate the efficacy in reducing canonical WNT/β-catenin signaling and the potential as an antiproliferative agent in this cancer cell line. Previously, we have shown that tankyrase inhibition can block WNT/β-catenin signaling and attenuate proliferation and viability in cancer cell lines in vitro and in vivo, including COLO 320DM that is commonly used for testing tankyrase inhibitors. (28,39,49,50) Treatment of COLO 320DM cells with 24 decreased viability with a GI50 value of 10.1 nM and a GI25 value of 2.5 nM (for 1, these values were 650 and 94 nM, respectively (39)), while APCwild-type RKO cells as a control colon cancer line were only modestly affected by treatment with compound 24 (Figure 4a). As previously observed upon tankyrase inhibition, (49,51) treatment with 24 dose-dependently either increased or decreased the TNKS1/2 protein levels (Figure 4b). Compound 24 also stabilized AXIN1 and AXIN2 proteins and reduced the level of transcriptionally active β-catenin (nonphosphorylated) in both cytoplasmic and nuclear fractions (Figure 4b). In addition, real-time qRT-PCR analyses revealed reduced levels of transcripts of the WNT/β-catenin signaling target genes AXIN2, DKK1, NKD1, and APCDD1 in a dose-dependent manner (Figure 4c). Collectively, these results showed that 24 both potently and specifically can inhibit WNT/β-catenin signaling activity and block proliferation in COLO 320DM cells.

Figure 4

Figure 4. Compound 24 decreased cell growth and inhibited WNT/β-catenin signaling activity in COLO 320DM cells. (a) 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) colorimetric cell growth assay for various doses of 24 in APCmutated COLO 320DM (black) and APCwild-type RKO (gray) cells. After 5 days, the antiproliferative effect of compound treatment was measured at 490 nm. Mean value ± standard deviation (SD) for one representative experiment of more than three repeated assays, each with six replicates, are shown. Dotted lines depict 50% (GI50-value) and 25% (GI25-value) growth inhibition levels and control = 100% (0.1% dimethyl sulfoxide (DMSO)). (b) Representative immunoblots of cytoplasmic TNKS1/2, AXIN1, AXIN2, and cytoplasmic and nuclear transcriptionally active β-catenin (non-phospho) and β-catenin. Actin and lamin B1 show equal protein loading, while # indicates that the same actin immunoblot is used as loading control for both AXIN2 and β-catenin. For (b) and (c), control = 0.001% DMSO. (c) Real-time RT-qPCR analyses of WNT/β-catenin signaling target genes (AXIN2, DKK1, NKD1, and APCDD1). Boxplots show median, first and third quartiles, and maximum and minimum whiskers for combined data from three independent experiments with three replicates each. Dotted lines depict the control mean value = 1. For (a) and (c), analysis of variance (ANOVA) tests (Holm–Sidak method, versus control) are indicated by *** (p < 0.001) and * (p < 0.05), while ANOVA on ranks tests (Dunn’s method, versus control) are indicated by † (p < 0.05).

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Conclusions

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In this further development of our structure-guided lead optimization program of 1,2,4-triazole-based tankyrase inhibitors, we have extensively improved previous lead compound 1 to lead candidate compound 24. (52) We showed that compound 24 possesses improved binding affinity in the catalytic pocket of the TNKS2 protein with concurrently modest selectivity over TNKS1, picomolar IC50 activity in the cellular WNT/β-catenin signaling reporter assay, a clean off-target safety profile, good ADME properties, an optimized mouse PK profile, and potent inhibition of WNT/β-catenin signaling and proliferation in COLO 320DM. These results justify testing compound 24 in a pharmacodynamics setting as well as in toxicity models (publication pending).

Experimental Section

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General Methods

NMR spectra were recorded on a 400 MHz spectrometer with tetramethylsilane as internal standards. Coupling constants are given in hertz. Peaks are reported as singlet (s), doublet (d), triplet (t), quartet (q), quintet (p), sextet (h), septet (hept), multiplet (m), or a combination thereof; br stands for broad.
Liquid chromatography/mass spectroscopy (LC/MS) chromatograms mass spectra were recorded using electrospray ionization (ESI) in positive or negative ionization mode on Agilent 1260 Bin: pump, G1312B, degasser; autosampler; ColCom; DAD G1315C; MSD G6130B ESI; eluent A, acetonitrile; eluent B, 10 mM ammonium bicarbonate in water (base mode) or 0.1% formic acid in water (acid mode). High-resolution mass spectra (HRMS) were recorded with an LC-MS Q Exactive Focus high-resolution mass spectrometer (Thermo Scientific). Calibration was done with the Pierce calibration solutions containing 1-butylamine, caffeine, MRFA, and Ultramark 1621 (positive mode) and the Pierce calibration solution containing sodium dodecyl sulfate, sodium taurocholate, and Ultramark 1621 (negative mode). Analysis: 1 μL of a 10 μg/mL sample in MeCN/DMSO 99:1 is injected and data are acquired under full MS mode (resolution 70 000 FWHM at 200 Da) over the mass range m/z of 150–2000. Standard ESI conditions compatible with the flow rate are applied: spray voltage, 3.5 kV; auxiliary gas heater temperature, 463 °C; capillary temperature, 280 °C; sheath gas, 58; auxiliary gas, 16; sweep gas, 3; S-lens radio frequency (RF) level, 50. Mass scan range is 150–2000 m/z. Mass resolution is set at 70 000 (<3 ppm mass accuracy). Data are evaluated using Xcalibur Qual Browser version 4.2.47 (Thermo Fisher).
All test compounds were >95% pure by LC/MS and 1H NMR analyses. All spectra as well as preparation of the intermediates and general procedures are given in the Supporting Experimentals.

N-(trans-3-(5-(5-Cyclopropoxypyridin-2-yl)-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (7)

The title compound was prepared according to general procedure F as a white solid (24.3 mg, 75%). LC/MS (ESI) m/z for C26H23N6O2F 470 (calculated) 471 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 8.56–8.49 (m, 1H), 8.26–8.13 (m, 3H), 7.99 (s, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.50–7.37 (m, 3H), 7.24–7.14 (m, 3H), 4.82–4.71 (m, 1H), 3.74 (tt, J = 6.1, 3.1 Hz, 1H), 3.46 (tt, J = 10.3, 5.3 Hz, 1H), 3.11–2.96 (m, 2H), 2.52–2.35 (m, 2H), 0.84–0.71 (m, 4H). HRMS m/z [M + H]+: 471.19393 (calculated), 471.1929 (found), Δ = −2.28 ppm.

N-(trans-3-(4-(2-Fluorophenyl)-5-(5-isopropoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (8)

The title compound was prepared according to general procedure F as a white solid (18.3 mg, 77%). LC/MS (ESI) m/z for C26H25N6O2F 472 (calculated) 473 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 8.57–8.48 (m, 1H), 8.21 (d, J = 6.9 Hz, 1H), 8.18–8.08 (m, 2H), 7.91–7.79 (m, 2H), 7.48–7.38 (m, 2H), 7.25–7.14 (m, 4H), 4.76 (h, J = 7.2 Hz, 1H), 4.54 (h, J = 6.0 Hz, 1H), 3.47 (tt, J = 10.1, 5.8 Hz, 1H), 3.11–2.97 (m, 2H), 2.52–2.36 (m, 2H), 1.32 (d, J = 6.0 Hz, 6H). HRMS m/z [M + H]+: 473.20958 (calculated), 473.2089 (found), Δ = −1.42 ppm.

N-(trans-3-(4-(2-Fluorophenyl)-5-phenyl-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (9)

The title compound was prepared according to general procedure F as a white solid (21 mg, 84%). LC/MS (ESI) m/z for C24H20N5OF 413 (calculated) 414 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 8.56–8.50 (m, 1H), 8.23 (d, J = 6.8 Hz, 1H), 8.17 (dt, J = 7.9, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.53–7.46 (m, 1H), 7.46–7.39 (m, 3H), 7.39–7.32 (m, 1H), 7.32–7.27 (m, 2H), 7.26–7.21 (m, 2H), 7.21–7.13 (m, 1H), 4.83–4.70 (m, 1H), 3.49 (tt, J = 10.2, 5.6 Hz, 1H), 3.11–2.95 (m, 2H), 2.52–2.40 (m, 2H). HRMS m/z [M + H]+: 414.17246 (calculated), 414.1714 (found), Δ = −2.46 ppm.

N-(trans-3-(4-(-2-Fluorophenyl)-5-(pyrazin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (10)

The title compound was prepared according to general procedure F as a white solid (7.9 mg, 21%). LC/MS (ESI) m/z for C22H18FN7O 415 (calculated) 416 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 9.52 (d, J = 1.8 Hz, 1H), 8.53 (d, J = 4.4 Hz, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.22–8.14 (m, 2H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.54–7.39 (m, 2H), 7.22 (td, J = 8.1, 7.5, 1.9 Hz, 3H), 4.83–4.74 (m, 1H), 3.52–3.46 (m, 1H), 3.07–3.02 (m, 1H), 2.56–2.41 (m, 2H), 1.55 (s, 2H). HRMS m/z [M + H]+: 416.16296 (calculated), 416.1620 (found), Δ = −2.40 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (11)

The title compound was prepared according to general procedure F as a white solid (30 mg, 52%). LC/MS (ESI) m/z for C25H24N6O2 440 (calculated) 441 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 8.53 (dq, J = 4.8, 1.1 Hz, 1H), 8.21 (d, J = 7.0 Hz, 1H), 8.16 (dt, J = 7.8, 1.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 2.9 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.46–7.38 (m, 4H), 7.21 (dd, J = 8.7, 2.9 Hz, 1H), 7.17–7.12 (m, 2H), 4.76 (h, J = 6.5 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.50 (dddd, J = 10.4, 8.9, 6.2, 5.0 Hz, 1H), 3.09–2.98 (m, 2H), 2.47–2.37 (m, 2H), 1.40 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 441.20335 (calculated), 441.2025 (found), Δ = −1.86 ppm.

N-(trans-3-(4-(3-Chlorophenyl)-5-(5-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (12)

The title compound was prepared according to general procedure F as a white solid (14.3 mg, 74%). LC/MS (ESI) m/z for C25H23N6O2Cl 474/476 (calculated) 475/477 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 8.53 (dt, J = 4.7, 1.3 Hz, 1H), 8.22 (d, J = 7.0 Hz, 1H), 8.17 (dt, J = 7.7, 1.0 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.46–7.40 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.7, 2.7 Hz, 1H), 7.18 (t, J = 2.0 Hz, 1H), 7.07 (dt, J = 8.0, 1.4 Hz, 1H), 4.78 (h, J = 7.0 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.53–3.42 (m, 1H), 3.09–2.97 (m, 2H), 2.51–2.39 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 475.16438 (calculated), 475.1636 (found), Δ = −1.73 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(5-methylthiophen-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (13)

The title compound was prepared according to general procedure F as a white solid (19 mg, 85%). LC/MS (ESI) m/z for C24H24N6O2S 460 (calculated) 461 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 8.57–8.52 (m, 1H), 8.25 (d, J = 7.1 Hz, 1H), 8.18 (dt, J = 7.8, 1.1 Hz, 1H), 8.12 (d, J = 2.9 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.43 (ddd, J = 7.7, 4.8, 1.3 Hz, 1H), 7.22 (dd, J = 8.7, 3.0 Hz, 1H), 6.70 (d, J = 3.6 Hz, 1H), 6.62 (dd, J = 3.6, 1.3 Hz, 1H), 4.78 (q, J = 7.1 Hz, 1H), 4.08 (q, J = 6.9 Hz, 2H), 3.65–3.56 (m, 1H), 3.11–3.01 (m, 2H), 2.56–2.49 (m, 2H), 2.47 (d, J = 1.1 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 461.17542 (calculated), 461.1746 (found), Δ = −1.85 ppm.

N-(trans-3-(4-(5-Chlorothiophen-2-yl)-5-(5-ethoxypyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)picolinamide (14)

The title compound was prepared according to general procedure F as a white solid (14.9 mg, 103%). LC/MS (ESI) m/z for C23H21N6O2SCl 480/482 (calculated) 481/483 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 8.55 (dt, J = 4.7, 1.4 Hz, 1H), 8.26 (d, J = 6.9 Hz, 1H), 8.18 (dt, J = 7.8, 1.1 Hz, 1H), 8.09 (d, J = 2.9 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.43 (ddd, J = 7.8, 4.7, 1.3 Hz, 1H), 7.25–7.20 (m, 1H), 6.82 (d, J = 4.0 Hz, 1H), 6.72 (d, J = 4.0 Hz, 1H), 4.79 (q, J = 7.2 Hz, 1H), 4.09 (q, J = 6.9 Hz, 2H), 3.63–3.56 (m, 1H), 3.11–3.01 (m, 2H), 2.59–2.48 (m, 2H), 1.43 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 481.12080 (calculated), 481.1201 (found), Δ = −1.14 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-1,5-naphthyridine-4-carboxamide (16a)

The title compound was prepared according to general procedure F as an off-white solid (13.7 mg, 55%). LC/MS (ESI) m/z for C27H24N8O2 492 (calculated) 493 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.32 (d, J = 6.0 Hz, 1H), 9.14 (d, J = 4.4 Hz, 1H), 8.99 (dd, J = 4.3, 1.8 Hz, 1H), 8.59–8.52 (m, 3H), 8.17 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 2.9 Hz, 1H), 7.79 (td, J = 7.7, 1.9 Hz, 1H), 7.75 (dd, J = 8.5, 4.2 Hz, 1H), 7.37 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 7.26–7.22 (m, 1H), 7.21–7.16 (m, 1H), 4.86–4.73 (m, 1H), 4.05 (q, J = 6.9 Hz, 2H), 3.80–3.69 (m, 1H), 3.11–3.01 (m, 2H), 2.57–2.46 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 493.20950 (calculated), 493.2085 (found), Δ = −1.99 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoro-1,5-naphthyridine-4-carboxamide (16b)

The title compound was prepared according to general procedure F as a white solid (17.9 mg, 69%). LC/MS (ESI) m/z for C27H23N8O2F 510 (calculated) 511 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.81 (d, J = 6.0 Hz, 1H), 9.15 (d, J = 4.5 Hz, 1H), 8.92 (d, J = 2.9 Hz, 1H), 8.56 (dd, J = 5.1, 1.9 Hz, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.22–8.18 (m, 1H), 8.17 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.79 (td, J = 7.7, 1.9 Hz, 1H), 7.37 (dd, J = 7.5, 4.8 Hz, 1H), 7.26–7.21 (m, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.80 (h, J = 6.9 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.72 (tt, J = 10.2, 5.3 Hz, 1H), 3.06 (ddd, J = 13.2, 8.0, 5.3 Hz, 2H), 2.50 (ddd, J = 12.6, 9.5, 6.2 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 511.20008 (calculated), 511.1991 (found), Δ = −1.86 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-1,5-naphthyridine-4-carboxamide (17a)

The title compound was prepared according to general procedure F as a white solid (12.6 mg, 50%). LC/MS (ESI) m/z for C27H24N8O2 492 (calculated) 493 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.31 (d, J = 6.0 Hz, 1H), 9.14 (d, J = 4.5 Hz, 1H), 8.98 (dd, J = 4.3, 1.8 Hz, 1H), 8.68 (dd, J = 4.8, 1.5 Hz, 1H), 8.59–8.52 (m, 2H), 8.48 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 2.9 Hz, 1H), 7.74 (dd, J = 8.6, 4.2 Hz, 1H), 7.58 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.41 (dd, J = 8.0, 4.7 Hz, 1H), 7.24 (dd, J = 8.7, 2.9 Hz, 1H), 4.86 (dtd, J = 8.7, 6.9, 5.2 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.58–3.47 (m, 1H), 3.14–3.03 (m, 2H), 2.62–2.51 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 493.20950 (calculated), 493.2084 (found), Δ = −2.32 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoro-1,5-naphthyridine-4-carboxamide (17b)

The title compound was prepared according to general procedure F as a white solid (22 mg, 85%). LC/MS (ESI) m/z for C27H23N8O2F 510 (calculated) 511 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.83 (d, J = 6.0 Hz, 1H), 9.15 (d, J = 4.4 Hz, 1H), 8.91 (d, J = 2.8 Hz, 1H), 8.69 (dd, J = 4.8, 1.5 Hz, 1H), 8.52 (d, J = 4.4 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.23–8.18 (m, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 2.8 Hz, 1H), 7.57 (dt, J = 8.1, 2.0 Hz, 1H), 7.41 (dd, J = 8.2, 4.8 Hz, 1H), 7.26–7.21 (m, 1H), 4.92–4.81 (m, 1H), 4.05 (q, J = 7.0 Hz, 2H), 3.56–3.45 (m, 1H), 3.14–3.03 (m, 2H), 2.60–2.50 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 511.20008 (calculated), 511.1991 (found), Δ = −1.95 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-1,5-naphthyridine-4-carboxamide (18a)

The title compound was prepared according to general procedure F as a white solid (12.7 mg, 51%). LC/MS (ESI) m/z for C27H24N8O2 492 (calculated) 493 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.31 (d, J = 6.0 Hz, 1H), 9.15 (d, J = 4.4 Hz, 1H), 8.97 (dd, J = 4.3, 1.8 Hz, 1H), 8.75–8.69 (m, 2H), 8.59–8.52 (m, 2H), 8.17 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.74 (dd, J = 8.5, 4.2 Hz, 1H), 7.26–7.22 (m, 1H), 7.17–7.11 (m, 2H), 4.92–4.81 (m, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.58–3.47 (m, 1H), 3.14–3.04 (m, 2H), 2.63–2.52 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 493.20950 (calculated), 493.2084 (found), Δ = −2.16 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoro-1,5-naphthyridine-4-carboxamide (18b)

The title compound was prepared according to general procedure F as a white solid (19.2 mg, 73%). LC/MS (ESI) m/z for C27H23N8O2F 510 (calculated) 511 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.83 (d, J = 6.0 Hz, 1H), 9.16 (d, J = 4.5 Hz, 1H), 8.91 (d, J = 2.9 Hz, 1H), 8.76–8.69 (m, 2H), 8.52 (d, J = 4.5 Hz, 1H), 8.20 (dd, J = 8.7, 2.9 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 7.91–7.85 (m, 1H), 7.26–7.22 (m, 1H), 7.17–7.10 (m, 2H), 4.87 (h, J = 7.1 Hz, 1H), 4.06 (q, J = 6.9 Hz, 2H), 3.56–3.45 (m, 1H), 3.14–3.03 (m, 2H), 2.62–2.51 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 511.20008 (calculated), 511.1992 (found), Δ = −1.69 ppm.

N-(3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)bicyclo[1.1.1]pentan-1-yl)-1,5-naphthyridine-4-carboxamide (19)

The title compound was prepared according to general procedure F as a white solid (12.1 mg, 47%). LC/MS (ESI) m/z for C28H24N8O2 504 (calculated) 505 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.46 (s, 1H), 9.14 (d, J = 4.5 Hz, 1H), 9.00 (dd, J = 4.3, 1.7 Hz, 1H), 8.63 (dd, J = 5.1, 1.8 Hz, 1H), 8.55 (dd, J = 8.6, 1.7 Hz, 1H), 8.50 (d, J = 4.4 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.87 (td, J = 7.7, 1.9 Hz, 1H), 7.84 (d, J = 3.0 Hz, 1H), 7.75 (dd, J = 8.6, 4.3 Hz, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.21 (dd, J = 8.7, 2.9 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 2.48 (s, 6H), 1.40 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 505.20950 (calculated), 505.2086 (found), Δ = −1.87 ppm.

N-(3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl)bicyclo[1.1.1]pentan-1-yl)-1,5-naphthyridine-4-carboxamide (20)

The title compound was prepared according to general procedure F as a white solid (20.2 mg, 78%). LC/MS (ESI) m/z for C28H24N8O2 504 (calculated) 505 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.45 (s, 1H), 9.14 (d, J = 4.5 Hz, 1H), 8.99 (dd, J = 4.1, 1.8 Hz, 1H), 8.74 (dd, J = 4.8, 1.5 Hz, 1H), 8.58–8.52 (m, 2H), 8.49 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 2.9 Hz, 1H), 7.74 (dd, J = 8.6, 4.3 Hz, 1H), 7.69 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.46 (dd, J = 8.0, 4.7 Hz, 1H), 7.22 (dd, J = 8.8, 2.9 Hz, 1H), 4.04 (q, J = 6.9 Hz, 2H), 2.49 (s, 6H), 1.40 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 505.20950 (calculated), 505.2085 (found), Δ = −2.01 ppm.

N-(3-(5-(5-Ethoxypyridin-2-yl)-4-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)bicyclo[1.1.1]pentan-1-yl)-1,5-naphthyridine-4-carboxamide (21)

The title compound was prepared according to general procedure F as a white solid (10.2 mg, 62%). LC/MS (ESI) m/z for C28H24N8O2 504 (calculated) 505 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.45 (s, 1H), 9.14 (d, J = 4.5 Hz, 1H), 8.99 (dd, J = 4.2, 1.8 Hz, 1H), 8.82–8.75 (m, 2H), 8.55 (dd, J = 8.6, 1.8 Hz, 1H), 8.50 (d, J = 4.4 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.74 (dd, J = 8.5, 4.2 Hz, 1H), 7.27 (d, J = 1.7 Hz, 2H), 7.23 (dd, J = 8.7, 2.9 Hz, 1H), 4.04 (q, J = 6.9 Hz, 2H), 2.51 (s, 6H), 1.41 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 505.20950 (calculated), 505.2085 (found), Δ = −2.02 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(5-methylthiophen-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-1,5-naphthyridine-4-carboxamide (22a)

The title compound was prepared according to general procedure F as a white solid (8.4 mg, 33%). LC/MS (ESI) m/z for C27H25N7O2S 511 (calculated) 512 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.31 (d, J = 6.0 Hz, 1H), 9.15 (d, J = 4.4 Hz, 1H), 9.00 (dd, J = 4.3, 1.8 Hz, 1H), 8.60–8.53 (m, 2H), 8.12 (d, J = 2.8 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.75 (dd, J = 8.5, 4.2 Hz, 1H), 7.23–7.20 (m, 1H), 6.72 (d, J = 3.7 Hz, 1H), 6.61 (dd, J = 3.7, 1.3 Hz, 1H), 4.86 (q, J = 7.0 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.72–3.62 (m, 1H), 3.16–3.05 (m, 2H), 2.69–2.58 (m, 2H), 2.47 (d, J = 1.1 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 512.18632 (calculated), 512.1854 (found), Δ = −1.73 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(5-methylthiophen-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoro-1,5-naphthyridine-4-carboxamide (22b)

The title compound was prepared according to general procedure F as a white solid (13 mg, 43%). LC/MS (ESI) m/z for C27H24N7O2SF 529 (calculated) 530 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.84 (d, J = 6.0 Hz, 1H), 9.16 (d, J = 4.4 Hz, 1H), 8.93 (d, J = 2.9 Hz, 1H), 8.54 (d, J = 4.4 Hz, 1H), 8.20 (dd, J = 8.7, 2.9 Hz, 1H), 8.12 (d, J = 2.9 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.23–7.19 (m, 1H), 6.72 (d, J = 3.7 Hz, 1H), 6.65–6.59 (m, 1H), 4.94–4.82 (m, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.72–3.60 (m, 1H), 3.15–3.06 (m, 2H), 2.66–2.57 (m, 2H), 2.47 (d, J = 1.1 Hz, 3H), 1.43 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 530.17690 (calculated), 530.1761 (found), Δ = −1.59 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(5-methylthiophen-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)quinoline-8-carboxamide (23)

The title compound was prepared according to general procedure F as a white solid (12 mg, 41%). LC/MS (ESI) m/z for C28H26N6O2S 510 (calculated) 511 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 11.57 (d, J = 5.9 Hz, 1H), 8.94 (dd, J = 4.2, 1.9 Hz, 1H), 8.85 (dd, J = 7.4, 1.6 Hz, 1H), 8.29 (dd, J = 8.3, 1.8 Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 7.96 (dd, J = 8.3, 1.6 Hz, 2H), 7.68 (t, J = 7.7 Hz, 1H), 7.53–7.47 (m, 1H), 7.22–7.19 (m, 1H), 6.72 (d, J = 3.7 Hz, 1H), 6.63–6.58 (m, 1H), 4.83 (q, J = 7.0 Hz, 1H), 4.08 (q, J = 7.0 Hz, 2H), 3.77–3.60 (m, 1H), 3.12–3.06 (m, 2H), 2.67–2.60 (m, 2H), 2.46 (d, J = 1.2 Hz, 3H), 1.43 (t, J = 6.9 Hz, 3H). HRMS m/z [M + H]+: 511.19107 (calculated), 511.1902 (found), Δ = −1.63 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)quinoxaline-5-carboxamide (24, OM-153)

The title compound was prepared according to general procedure F as a white solid (20.4 mg, 79%). LC/MS (ESI) m/z for C28H24N7O2F 509 (calculated) 510 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.68 (d, J = 5.9 Hz, 1H), 8.97 (d, J = 1.9 Hz, 1H), 8.89–8.83 (m, 2H), 8.26 (dd, J = 8.3, 1.6 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.94–7.86 (m, 2H), 7.47–7.39 (m, 1H), 7.25–7.13 (m, 4H), 4.83 (dqd, J = 8.5, 6.8, 5.3 Hz, 1H), 4.04 (q, J = 7.0 Hz, 2H), 3.53 (dp, J = 10.1, 5.5 Hz, 1H), 3.08 (dtd, J = 12.0, 5.8, 3.9 Hz, 2H), 2.53 (ddtt, J = 19.4, 9.6, 6.2, 3.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 510.20483 (calculated), 510.2040 (found), Δ = −1.66 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoroquinoxaline-5-carboxamide (25)

The title compound was prepared according to general procedure F as a white solid (18.2 mg, 68%). LC/MS (ESI) m/z for C28H23N7O2F 527 (calculated) 528 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.62 (d, J = 5.8 Hz, 1H), 8.96 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.9 Hz, 1H), 8.64 (dd, J = 9.6, 3.1 Hz, 1H), 8.24–8.11 (m, 1H), 7.87 (dd, J = 7.9, 3.1 Hz, 2H), 7.48–7.39 (m, 1H), 7.25–7.14 (m, 4H), 4.83 (h, J = 6.8 Hz, 1H), 4.04 (q, J = 6.9 Hz, 2H), 3.57–3.46 (m, 1H), 3.13–3.01 (m, 2H), 2.60–2.45 (m, 2H), 1.40 (t, J = 6.9 Hz, 3H). HRMS m/z [M + H]+: 528.19541 (calculated), 528.1946 (found), Δ = −1.59 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-3-methylquinoxaline-5-carboxamide (26)

The title compound was prepared according to general procedure F as a slightly pink solid (93.1 mg, 65%). LC/MS (ESI) m/z for C29H26N7O2F 523 (calculated) 524 ([M + H]+, found). 1H NMR (400 MHz, DMSO) δ 10.42 (d, J = 7.1 Hz, 1H), 8.98 (s, 1H), 8.41 (dd, J = 7.3, 1.5 Hz, 1H), 8.21 (dd, J = 8.3, 1.5 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 3.0 Hz, 1H), 7.87 (dd, J = 8.3, 7.3 Hz, 1H), 7.61–7.53 (m, 2H), 7.50 (dd, J = 8.8, 3.0 Hz, 1H), 7.47–7.39 (m, 1H), 7.36–7.29 (m, 1H), 4.75 (q, J = 7.3 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.40 (dt, J = 9.4, 4.6 Hz, 1H), 2.92–2.82 (m, 1H), 2.75 (s, 3H), 2.72–2.66 (m, 1H), 2.45–2.29 (m, 2H), 1.31 (t, J = 6.9 Hz, 3H). HRMS m/z [M + H]+: 524.22048 (calculated), 524.2197 (found), Δ = −1.56 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-methylquinoxaline-5-carboxamide (27)

The title compound was prepared according to general procedure F as an off-white solid (20.1 mg, 71%). LC/MS (ESI) m/z for C29H26N7O2F 523 (calculated) 524 ([M + H]+, found). 1H NMR (400 MHz, DMSO) δ 10.42 (d, J = 7.1 Hz, 1H), 8.98 (s, 1H), 8.41 (dd, J = 7.3, 1.6 Hz, 1H), 8.21 (dd, J = 8.4, 1.5 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.8 Hz, 1H), 7.91–7.84 (m, 1H), 7.63–7.52 (m, 2H), 7.50 (dd, J = 8.8, 3.0 Hz, 1H), 7.47–7.39 (m, 1H), 7.36–7.29 (m, 1H), 4.75 (q, J = 7.2 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.44–3.36 (m, 1H), 2.87 (q, J = 3.8 Hz, 1H), 2.75 (s, 3H), 2.68 (s, 1H), 2.45–2.28 (m, 2H), 1.31 (t, J = 6.9 Hz, 3H). HRMS m/z [M + H]+: 524.22048 (calculated), 524.2198 (found), Δ = −1.36 ppm.

N-(trans-3-(5-(5-Ethoxypyridin-2-yl)-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-2,3-dimethylquinoxaline-5-carboxamide (28)

The title compound was prepared according to general procedure F as an off-white solid (29.7 mg, 43%). LC/MS (ESI) m/z for C30H28N7O2F 537 (calculated) 538 ([M + H]+, found). 1H NMR (400 MHz, DMSO) δ 10.59 (d, J = 7.2 Hz, 1H), 8.36 (dd, J = 7.4, 1.6 Hz, 1H), 8.18–8.01 (m, 2H), 7.94 (d, J = 3.0 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.56 (td, J = 8.2, 3.1 Hz, 2H), 7.50 (dd, J = 8.8, 2.9 Hz, 1H), 7.43 (t, J = 9.2 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 4.75 (q, J = 7.2 Hz, 1H), 4.10 (q, J = 7.0 Hz, 2H), 2.86 (d, J = 9.7 Hz, 1H), 2.72 (d, J = 3.6 Hz, 7H), 2.45–2.28 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H). HRMS m/z [M + H]+: 538.23613 (calculated), 538.2349 (found), Δ = −2.27 ppm.

N-(trans-3-(5-(5-(Difluoromethoxy)pyridin-2-yl)-4-(2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)quinoxaline-5-carboxamide (29a)

The title compound was prepared according to general procedure F as a white solid (23 mg, 86%). LC/MS (ESI) m/z for C27H20N7O2F3 531 (calculated) 532 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.67 (d, J = 5.9 Hz, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.89–8.83 (m, 2H), 8.33 (d, J = 8.8 Hz, 1H), 8.26 (dd, J = 8.4, 1.6 Hz, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.90 (dd, J = 8.4, 7.4 Hz, 1H), 7.55 (dd, J = 8.8, 2.8 Hz, 1H), 7.51–7.42 (m, 1H), 7.26–7.16 (m, 3H), 6.52 (t, J = 72.5 Hz, 1H), 4.90–4.79 (m, 1H), 3.57–3.47 (m, 1H), 3.14–3.02 (m, 2H), 2.63–2.47 (m, 2H). HRMS m/z [M + H]+: 532.17033 (calculated), 532.1692 (found), Δ = −2.12 ppm.

N-(trans-3-(5-(5-(2,2-Difluoroethoxy)pyridin-2-yl)-4-((S)-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoroquinoxaline-5-carboxamide (29b)

The title compound was prepared according to general procedure F as a white solid (19.8 mg, 71%). LC/MS (ESI) m/z for C27H19N7O2F4 549 (calculated) 550 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.63 (d, J = 5.9 Hz, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.82 (d, J = 1.9 Hz, 1H), 8.64 (dd, J = 9.5, 3.1 Hz, 1H), 8.33 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 7.8, 3.1 Hz, 1H), 7.55 (dd, J = 8.8, 2.8 Hz, 1H), 7.51–7.42 (m, 1H), 7.25–7.16 (m, 3H), 6.52 (t, J = 72.5 Hz, 1H), 4.91–4.79 (m, 1H), 3.56–3.45 (m, 1H), 3.14–3.01 (m, 2H), 2.62–2.47 (m, 2H). HRMS m/z [M + H]+: 550.16091 (calculated), 550.1597 (found), Δ = −2.25 ppm.

N-(trans-3-(4-(2-Fluorophenyl)-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)quinoxaline-5-carboxamide (30a)

The title compound was prepared according to general procedure F as a white solid (19.3 mg, 83%). LC/MS (ESI) m/z for C26H20N7OG 465 (calculated) 466 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.68 (d, J = 5.8 Hz, 1H), 8.97 (d, J = 1.8 Hz, 1H), 8.89–8.83 (m, 2H), 8.26 (dd, J = 8.3, 1.5 Hz, 2H), 8.24–8.18 (m, 1H), 7.94–7.87 (m, 1H), 7.76 (td, J = 7.8, 1.7 Hz, 1H), 7.49–7.40 (m, 1H), 7.25–7.14 (m, 4H), 4.90–4.78 (m, 1H), 3.59–3.49 (m, 1H), 3.15–3.03 (m, 2H), 2.62–2.47 (m, 2H). HRMS m/z [M + H]+: 466.17861 (calculated), 466.1775 (found), Δ = −2.34 ppm.

N-(trans-3-(5-(5-(6-Methylpyridin-2-yl)-4-(S)-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoroquinoxaline-5-carboxamide (30b)

The title compound was prepared according to general procedure F as a white solid (16 mg, 65%). LC/MS (ESI) m/z for C26H19N7OF2 483 (calculated) 484 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.63 (d, J = 5.8 Hz, 1H), 8.96 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.64 (dd, J = 9.6, 3.1 Hz, 1H), 8.26 (dt, J = 8.1, 1.1 Hz, 1H), 8.22 (dd, J = 4.8, 1.6 Hz, 1H), 7.87 (dd, J = 7.8, 3.1 Hz, 1H), 7.76 (td, J = 7.8, 1.8 Hz, 1H), 7.49–7.40 (m, 1H), 7.25–7.14 (m, 4H), 4.84 (ht, J = 7.1, 1.5 Hz, 1H), 3.53 (tt, J = 9.3, 5.3 Hz, 1H), 3.14–3.02 (sym. m, 2H), 2.55 (dddd, J = 16.5, 13.1, 9.8, 6.5 Hz, 2H). HRMS m/z [M + H]+: 484.16919 (calculated), 484.1684 (found), Δ = −1.65 ppm.

N-(trans-3-(4-(2-Fluorophenyl)-5-(6-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)quinoxaline-5-carboxamide (31a)

The title compound was prepared according to general procedure F as a white solid (20.7 mg, 86%). LC/MS (ESI) m/z for C27H22N7OF 479 (calculated) 480 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.68 (d, J = 5.7 Hz, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.90–8.82 (m, 2H), 8.26 (dd, J = 8.4, 1.6 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.90 (dd, J = 8.4, 7.4 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.49–7.41 (m, 1H), 7.26–7.14 (m, 3H), 7.03 (d, J = 7.7 Hz, 1H), 4.89–4.78 (m, 1H), 3.61–3.50 (m, 1H), 3.15–3.05 (m, 2H), 2.62–2.48 (m, 2H), 2.07 (s, 3H). HRMS m/z [M + H]+: 480.19426 (calculated), 480.1934 (found), Δ = −1.75 ppm.

N-(trans-3-(4-(2-Fluorophenyl)-5-(6-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-7-fluoroquinoxaline-5-carboxamide (31b)

The title compound was prepared according to general procedure F as a white solid (18.2 mg, 72%). LC/MS (ESI) m/z for C27H21N7OF2 497 (calculated) 498 ([M + H]+, found). 1H NMR (400 MHz, CDCl3) δ 10.63 (d, J = 5.9 Hz, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.64 (dd, J = 9.5, 3.1 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 7.87 (dd, J = 7.8, 3.1 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.49–7.41 (m, 1H), 7.24–7.15 (m, 3H), 7.03 (d, J = 7.7 Hz, 1H), 4.91–4.78 (m, 1H), 3.60–3.49 (m, 1H), 3.15–3.03 (m, 2H), 2.62–2.48 (m, 2H), 2.07 (s, 3H). HRMS m/z [M + H]+: 498.18484 (calculated), 498.1838 (found), Δ = −2.11 ppm.

Biochemical Assay

Recombinantly expressed human tankyrase active constructs for TNKS1 (residues 1030–1317) and TNKS2 (residues 873–1162) and other PARP enzymes used for biochemical assays were produced as previously described. (39) The enzymatic assay measures unreacted NAD+, which is chemically reacted into a fluorescent compound. (53) The fluorescence intensity was measured with excitation/emission wavelengths of 372 and 444 nm, respectively, using Tecan Infinity M1000 Pro. New compounds were prepared in half-log dilution series, and the reactions were carried out in quadruplicates with protein and compound controls to exclude the effect of compound autofluorescence. All reactions were performed at ambient temperature. TNKS1 (20 nM) or TNKS2 (5 nM) was incubated for 20 h in assay buffer (50 mM Bis-Tris propane (BTP), pH 7.0, 0.5 mM Tris(2-carboxyethyl)phosphine (TCEP), 0.01% Triton X-100) with compound and 10 μM or 500 nM NAD+, respectively.
The assay conditions for the other PARP enzymes were used as previously described. (39) Reference compound OD336 behaved in this assay as previously reported. (28)
For single IC50 curves, the 95% confidence interval (asymptotic) was calculated in GraphPad Prism 8.

WNT/β-Catenin Signaling Reporter Assay

The luciferase based WNT/β-catenin signaling pathway reporter assay in human HEK293 cells was performed in triplicates as previously described (21) also taking OD336 as a reference compound, which behaved in this assay as previously described. (28)

ADME

Kinetic solubility, microsomal stability, and plasma stability were determined following our internal protocol (Symeres). The Caco-2 and PPB determinations were performed by Cyprotex.

Off-Target

A safety panel (Cerep) of 44 selected targets (n = 2) including hERG Inhibition using 10 μM 24 was performed by Eurofins. Ames and CYP3A4 inhibition assays were performed by Cyprotex, and the PXR assay (CYP induction) was performed at Admescope. The PARP assays are described below.

Mouse Pharmacokinetic Analysis

The pharmacokinetic analyses in mice were performed according to the standard protocols of Medicilon as previously described (21) following approval by local animal experiment authorities (Shanghai, China) and in compliance with FELASA guidelines and recommendations. Three IRC mice were used per treatment group: 5 mg/kg 24 in 5% DMSO, 50% PEG400 (both Sigma-Aldrich), and 45% saline as vehicle. Samples were collected after 5, 15, and 30 min and 1, 2, 4, 8, and 24 h.

Crystallography

The co-crystallization of human TNKS2 catalytic domain (residues 952–1161) in complex with 24 was done in the presence of chymotrypsin (1:100) and based on crystallization efforts previously described. (39) Protein (5.3 mg/mL) was mixed with 0.4 mM compound from a 10 mM stock solution in DMSO. The droplets for crystallization were set up using the sitting-drop vapor diffusion method by mixing 200 nL of protein with 100 nL of precipitant solution (0.1 M Bicine, pH 8.5–9.0, 7.5–25% PEG6000). All steps were performed at room temperature. Rod-shaped crystals appeared within 24 h and were cryoprotected using the precipitant solution containing 25% PEG6000 and 20% glycerol. Data were collected at Diamond Light Source on beamline I04. Diffraction data were processed using the XDS package. (54) The substructure was solved using molecular replacement with PHASER (55) using the structure of TNKS2 (PDB code: 5NOB) as starting model. Model building and refinement was done using Coot (56) and Refmac5, (57) respectively. Preparation of the crystal structure images was done with The PyMOL Molecular Graphics System (PyMOL, version 1.8.4.0).

Proliferation Assay

Antiproliferative assays using colon cancer cell lines COLO 320DM and RKO were performed as previously described. (39)

Western Blot Analysis

Western blot analysis of nuclear and cytoplasmic lysates from compound-treated COLO 320DM cells was performed as previously described. (39,50)

RNA Isolation and Real-Time qRT-PCR

RNA isolation and real-time qRT-PCR were performed as previously described. (39,50)

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01264.

  • Molecular formula strings and data (CSV)

  • General and specific synthetic procedures and spectra for all compounds and inhibition data and crystallography; atomic coordinates and structure factors have been deposited to the Protein Data Bank under accession number 7O6X, and raw diffraction images are available at IDA (https://doi.org/10.23729/4d448eb0-c6ef-4b7d-a557-3758f5f68d47). The authors will release the atomic coordinates upon article publication (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
    • Stefan Krauss - Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway;  Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway;  Email: [email protected]
  • Authors
    • Ruben G. G. Leenders - Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands;  Orcidhttps://orcid.org/0000-0001-6140-5405
    • Shoshy Alam Brinch - Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway;  Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway
    • Sven T. Sowa - Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
    • Enya Amundsen-Isaksen - Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway;  Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway
    • Albert Galera-Prat - Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
    • Sudarshan Murthy - Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
    • Sjoerd Aertssen - Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
    • Johannes N. Smits - Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
    • Piotr Nieczypor - Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
    • Eddy Damen - Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
    • Anita Wegert - Symeres, Kerkenbos 1013, 6546 BB Nijmegen, The Netherlands
    • Marc Nazaré - Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin Buch, Robert-Roessle-Str. 10, 13125 Berlin, Germany;  Orcidhttps://orcid.org/0000-0002-1602-2330
    • Lari Lehtiö - Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland;  Orcidhttps://orcid.org/0000-0001-7250-832X
    • Jo Waaler - Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway;  Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0424 Oslo, Norway;  Orcidhttps://orcid.org/0000-0002-8501-6225
  • Author Contributions

    R.G.G.L. and S.A.B. contributed equally to this article, while J.W. and S.K. contributed equally as co-senior authors of this article. The manuscript was written through contributions of all authors, and all authors have given approval to the final version of the manuscript.

  • Funding

    S.K. was supported by the Research Council of Norway (grant nos. 262613 and 267639) and by South-Eastern Norway Regional Health Authority (grant nos. 16/00528-9, 15/00779-2, and 2015012). S.A.B. and J.W. were supported by the South-Eastern Norway Regional Health Authority (grant nos. 2019090 and 2021035). L.L., S.T.S., A.G.-P., and S.M. were supported by the Jane and Aatos Erkko Foundation, Sigrid Jusélius Foundation and Academy of Finland (grant nos. 287063, 294085, and 319299).

  • Notes
    The authors declare the following competing financial interest(s): J.W., M.N., L.L., A.W., R.G.G.L., and S.K. hold patents related to tankyrase inhibitor therapy, and these authors declare no additional interests. The remaining authors declare no competing interests.

Acknowledgments

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Heli Alanen is acknowledged for her contribution in performing some of the biochemical assays. Ilonka Meerts and Eef van den Elzen, both of Symeres, are acknowledged for their contributions with the ADME assays and the HRMS. Peter Zenhorst (Symeres) is acknowledged for the development of a CMC route for compound 24. Protein crystallography experiments were performed at the Diamond Light Source (Didcot, U.K.) on beamline I04. The authors are grateful to local contacts for providing assistance in using the beamlines. The use of the facilities and expertise of the Biocenter Oulu Protein Crystallography core facility, a member of Biocenter Finland and Instruct-FI, is gratefully acknowledged.

Abbreviations Used

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ADME

absorption, distribution, metabolism, and excretion

ADP

adenosine 5′-diphosphate

AKT

serine/threonine kinase

AMOT

angiomotin

AMP

adenosine monophosphate

AMPK

AMP-activated protein kinase

APC

adenomatous polyposis coli

APCDD1

APC downregulated 1

AUC

area under the curve

AXIN

axis inhibition protein

CL

clearance

CMC

chemistry, manufacturing, and control

DKK1

dickkopf WNT signaling pathway inhibitor 1

DMSO

dimethyl sulfoxide

HEK293

human embryonic kidney 293

hERG

human ether-à-go-go-related gene

LC/MS

liquid chromatography/mass spectroscopy

MTS

3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

NKD1

NKD inhibitor of WNT signaling pathway 1

NAD

nicotinamide adenine dinucleotide

NMR

nuclear magnetic resonance

PARP

poly-ADP-ribose polymerase

PARsylate

poly(ADP-ribose)sylate

PGC-1α

peroxisome proliferator-activated receptor-γ coactivator 1 α

PK

pharmacokinetics

PO

per oral

PPB

plasma protein binding

PTEN

phosphatase and tensin homolog

RT-qPCR

reverse transcription quantitative polymerase chain reaction

RNF146

ring finger protein 146

SD

standard deviation

SEM

standard error of the mean

SH3BP2

sarcoma homology 3 (SH3) domain binding protein 2

SOX9

sex-determining region Y (SRY)-box transcription factor 9

t1/2

half-life

TNKS

telomeric repeat factor (TRF1)-interacting ankyrin-related ADP-ribose polymerases, tankyrase

TNKS1/2

tankyrase 1 and tankyrase 2

tPSA

total polar surface area

TRF

telomeric repeat factor

Vd

volume of distribution

WNT

wingless-type mammary tumor virus integration site

References

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This article references 57 other publications.

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    Zhang, Y.; Liu, S.; Mickanin, C.; Feng, Y.; Charlat, O.; Michaud, G. A.; Schirle, M.; Shi, X.; Hild, M.; Bauer, A.; Myer, V. E.; Finan, P. M.; Porter, J. A.; Huang, S.-M. A.; Cong, F. RNF146 Is a Poly(ADP-Ribose)-Directed E3 Ligase That Regulates Axin Degradation and Wnt Signalling. Nat. Cell Biol. 2011, 13, 623– 629,  DOI: 10.1038/ncb2222
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    RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling
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    Nature Cell Biology (2011), 13 (5), 623-629CODEN: NCBIFN; ISSN:1465-7392. (Nature Publishing Group)
    The Wnt/β-catenin signalling pathway plays essential roles in embryonic development and adult tissue homeostasis, and deregulation of this pathway has been linked to cancer. Axin is a concn.-limiting component of the β-catenin destruction complex, and its stability is regulated by tankyrase. However, the mol. mechanism by which tankyrase-dependent poly(ADP-ribosyl)ation (PARsylation) is coupled to ubiquitylation and degrdn. of axin remains undefined. Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a pos. regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degrdn. of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degrdn. of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degrdn. Thus, identification of RNF146 as a PARsylation-directed E3 ligase establishes a mol. paradigm that links tankyrase-dependent PARsylation to ubiquitylation. RNF146-dependent protein degrdn. may emerge as a major mechanism by which tankyrase exerts its function.
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  2. 2
    Callow, M. G.; Tran, H.; Phu, L.; Lau, T.; Lee, J.; Sandoval, W. N.; Liu, P. S.; Bheddah, S.; Tao, J.; Lill, J. R.; Hongo, J.-A.; Davis, D.; Kirkpatrick, D. S.; Polakis, P.; Costa, M. Ubiquitin Ligase RNF146 Regulates Tankyrase and Axin to Promote Wnt Signaling. PLoS One 2011, 6, e22595– e22608,  DOI: 10.1371/journal.pone.0022595
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    2
    Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling
    Callow, Marinella G.; Tran, Hoanh; Phu, Lilian; Lau, Ted; Lee, James; Sandoval, Wendy N.; Liu, Peter S.; Bheddah, Sheila; Tao, Janet; Lill, Jennie R.; Hongo, Jo-Anne; Davis, David; Kirkpatrick, Donald S.; Polakis, Paul; Costa, Mike
    PLoS One (2011), 6 (7), e22595CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Canonical Wnt signaling is controlled intracellularly by the level of β-catenin protein, which is dependent on Axin scaffolding of a complex that phosphorylates β-catenin to target it for ubiquitylation and proteasomal degrdn. This function of Axin is counteracted through relocalization of Axin protein to the Wnt receptor complex to allow for ligand-activated Wnt signaling. AXIN1 and AXIN2 protein levels are regulated by tankyrase-mediated poly(ADP-ribosyl)ation (PARsylation), which destabilizes Axin and promotes signaling. Mechanistically, how tankyrase limits Axin protein accumulation, and how tankyrase levels and activity are regulated for this function, are currently under investigation. By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a pos. regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. RNF146 also destabilizes tankyrases TNKS1 and TNKS2 proteins and, in a reciprocal relationship, tankyrase activity reduces RNF146 protein levels. We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all 3 proteins to target them for proteasomal degrdn. RNF146 is a cytoplasmic protein that also prevents tankyrase protein aggregation at a centrosomal location. Tankyrase auto-PARsylation and PARsylation of Axin is known to lead to proteasome-mediated degrdn. of these proteins, and we demonstrate that, through ubiquitylation, RNF146 mediates this process to regulate Wnt signaling.
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  3. 3
    Haikarainen, T.; Kraus, S.; Lehtiö, L. Tankyrases: Structure, Function and Therapeutic Implications in Cancer. Curr. Pharm. Des. 2014, 20, 6472– 6488,  DOI: 10.2174/1381612820666140630101525
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    3
    Tankyrases: Structure, Function and Therapeutic Implications in Cancer
    Haikarainen, Teemu; Krauss, Stefan; Lehtio, Lari
    Current Pharmaceutical Design (2014), 20 (41), 6472-6488CODEN: CPDEFP; ISSN:1381-6128. (Bentham Science Publishers Ltd.)
    A review. Several cellular signaling pathways are regulated by ADP-ribosylation, a posttranslational modification catalyzed by members of the ARTD superfamily. Tankyrases are distinguishable from the rest of this family by their unique domain organization, notably the sterile alpha motif responsible for oligomerization and ankyrin repeats mediating protein-protein interactions. Tankyrases are involved in various cellular functions, such as telomere homeostasis, Wnt/β -catenin signaling, glucose metab., and cell cycle progression. In these processes, Tankyrases regulate the interactions and stability of target proteins by poly (ADP-ribosyl)ation. Modified proteins are subsequently recognized by the E3 ubiquitin ligase RNF146, poly-ubiquitinated and predominantly guided to 26S proteasomal degrdn. Several small mol. inhibitors have been described for Tankyrases; they compete with the co-substrate NAD+ for binding to the ARTD catalytic domain. The recent, highly potent and selective inhibitors possess several properties of lead compds. and can be used for proof-of-concept studies in cancer and other Tankyrase linked diseases.
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  4. 4
    Nie, L.; Wang, C.; Li, N.; Feng, X.; Lee, N.; Su, D.; Tang, M.; Yao, F.; Chen, J. Proteome-Wide Analysis Reveals Substrates of E3 Ligase RNF146 Targeted for Degradation. Mol. Cell. Proteomics 2020, 19, 2015– 2030,  DOI: 10.1074/mcp.RA120.002290
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    4
    Proteome-wide analysis reveals substrates of E3 ligase RNF146 targeted for degradation
    Nie, Litong; Wang, Chao; Li, Nan; Feng, Xu; Lee, Namsoo; Su, Dan; Tang, Mengfan; Yao, Fan; Chen, Junjie
    Molecular & Cellular Proteomics (2020), 19 (12), 2015-2029CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
    Specific E3 ligases target tumor suppressors for degrdation. Inhibition of such E3 ligases may be an important approach to cancer treatment. RNF146 is a RING domain and PARylation-dependent E3 ligase that functions as an activator of the β-catenin/Wnt and YAP/Hippo pathways by targeting the degrdation of several tumor suppressors. Tankyrases 1 and 2 (TNKS1/2) are the only known poly-ADP-ribosyltransferases that require RNF146 to degrade their substrates. However, systematic identification of RNF146 substrates have not yet been performed. To uncover substrates of RNF146 that are targeted for degrdation, we generated RNF146 knockout cells and TNKS1/2-double knockout cells and performed proteome profiling with label-free quantification as well as transcriptome anal. We identified 160 potential substrates of RNF146, which included many known substrates of RNF146 and TNKS1/2 and 122 potential TNKS-independent substrates of RNF146. In addn., we validated OTU domain-contg. protein 5 and Protein mono-ADP-ribosyltransferase PARP10 as TNKS1/2-independent substrates of RNF146 and SARDH as a novel substrate of TNKS1/2 and RNF146. Our study is the first proteome-wide anal. of potential RNF146 substrates. Together, these findings not only demonstrate that proteome profiling can be a useful general approach for the systemic identification of substrates of E3 ligases but also reveal new substrates of RNF146, which provides a resource for further functional studies.
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  5. 5
    Seimiya, H.; Smith, S. The Telomeric Poly(ADP-Ribose) Polymerase, Tankyrase 1, Contains Multiple Binding Sites for Telomeric Repeat Binding Factor 1 (TRF1) and a Novel Acceptor, 182-KDa Tankyrase-Binding Protein (TAB182)*. J. Biol. Chem. 2002, 277, 14116– 14126,  DOI: 10.1074/jbc.M112266200
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    5
    The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182)
    Seimiya, Hiroyuki; Smith, Susan
    Journal of Biological Chemistry (2002), 277 (16), 14116-14126CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    Tankyrase 1, a human telomeric poly(ADP-ribose) polymerase, was originally identified through its interaction with TRF1, a neg. regulator of telomere length. Tankyrase 1 ADP-ribosylates TRF1 in vitro, and its over-expression induces telomere elongation in human cancer cells. In addn. to its telomeric localization, tankyrase 1 resides at multiple subcellular sites, suggesting addnl. functions for this protein. Here the authors identify TAB182, a novel tankyrase 1-binding protein of 182 kDa. TAB182 displays a complex pattern of subcellular localization. TAB182 localizes to the nucleus in a heterochromatic staining pattern and to the cytoplasm, where it co-stains with the cortical actin network. TAB182 coimmunoppts. with tankyrase 1 from human cells and serves as an acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in vitro. Like TRF1, TAB182 binds to the ankyrin domain (comprising 24 ankyrin repeats) of tankyrase 1. Surprisingly, dissection of this domain reveals multiple discrete and overlapping binding sites for TRF1 and TAB182. Thus, the authors demonstrate five well conserved ankyrin repeat clusters in tankyrase 1. Although each of the five ankyrin repeat clusters independently binds to TRF1, only three of the five bind to TAB182. These findings suggest that tankyrase 1 may act as a scaffold for large mol. mass complexes made up of multiple binding proteins. The authors discuss potential roles for tankyrase 1-mediated higher order complexes at telomeres and at other subcellular sites.
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  6. 6
    Mariotti, L.; Templeton, C. M.; Ranes, M.; Paracuellos, P.; Cronin, N.; Beuron, F.; Morris, E.; Guettler, S. Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling. Mol. Cell 2016, 63, 498– 513,  DOI: 10.1016/j.molcel.2016.06.019
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    6
    Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling
    Mariotti, Laura; Templeton, Catherine M.; Ranes, Michael; Paracuellos, Patricia; Cronin, Nora; Beuron, Fabienne; Morris, Edward; Guettler, Sebastian
    Molecular Cell (2016), 63 (3), 498-513CODEN: MOCEFL; ISSN:1097-2765. (Elsevier Inc.)
    The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymg. TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochem. studies informed by these structures demonstrate that polymn. is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling.
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  7. 7
    Pollock, K.; Liu, M.; Zaleska, M.; Meniconi, M.; Pfuhl, M.; Collins, I.; Guettler, S. Fragment-Based Screening Identifies Molecules Targeting the Substrate-Binding Ankyrin Repeat Domains of Tankyrase. Sci. Rep. 2019, 9, 19130  DOI: 10.1038/s41598-019-55240-5
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    7
    Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase
    Pollock, Katie; Liu, Manjuan; Zaleska, Mariola; Meniconi, Mirco; Pfuhl, Mark; Collins, Ian; Guettler, Sebastian
    Scientific Reports (2019), 9 (1), 19130CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A no. of these are implicated in cancer-relevant processes, including Wnt/β-catenin signaling, Hippo signaling and telomere maintenance. The ARCs recognize a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase's poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent "scaffolding" mechanisms contribute to tankyrase function. Here we report a fragment-based screening program against tankyrase ARC domains, using a combination of biophys. assays, including differential scanning fluorimetry (DSF) and NMR (NMR) spectroscopy. We identify fragment mols. that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compds. will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.
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  8. 8
    Perdreau-Dahl, H.; Progida, C.; Barfeld, S. J.; Guldsten, H.; Thiede, B.; Arntzen, M.; Bakke, O.; Mills, I. G.; Krauss, S.; Morth, J. P. Sjögren Syndrome/Scleroderma Autoantigen 1 Is a Direct Tankyrase Binding Partner in Cancer Cells. Commun. Biol. 2020, 3, 123  DOI: 10.1038/s42003-020-0851-2
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    8
    Sjogren syndrome/scleroderma autoantigen 1 is a direct Tankyrase binding partner in cancer cells
    Perdreau-Dahl Harmonie; Guldsten Hanne; Morth J Preben; Perdreau-Dahl Harmonie; Morth J Preben; Progida Cinzia; Bakke Oddmund; Barfeld Stefan J; Mills Ian G; Thiede Bernd; Arntzen Magnus; Mills Ian G; Mills Ian G; Krauss Stefan; Morth J Preben
    Communications biology (2020), 3 (1), 123 ISSN:.
    Sjogren syndrome/scleroderma autoantigen 1 (SSSCA1) was first described as an auto-antigen over-expressed in Sjogren's syndrome and in scleroderma patients. SSSCA1 has been linked to mitosis and centromere association and as a potential marker candidate in diverse solid cancers. Here we characterize SSSCA1 for the first time, to our knowledge, at the molecular, structural and subcellular level. We have determined the crystal structure of a zinc finger fold, a zinc ribbon domain type 2 (ZNRD2), at 2.3 ÅA resolution. We show that the C-terminal domain serves a dual function as it both behaves as the interaction site to Tankyrase 1 (TNKS1) and as a nuclear export signal. We identify TNKS1 as a direct binding partner of SSSCA1, map the binding site to TNKS1 ankyrin repeat cluster 2 (ARC2) and thus define a new binding sequence. We experimentally verify and map a new nuclear export signal sequence in SSSCA1.
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  9. 9
    Wang, H.; Kuusela, S.; Rinnankoski-Tuikka, R.; Dumont, V.; Bouslama, R.; Ramadan, U. A.; Waaler, J.; Linden, A.-M.; Chi, N.-W.; Krauss, S.; Pirinen, E.; Lehtonen, S. Tankyrase Inhibition Ameliorates Lipid Disorder via Suppression of PGC-1α PARylation in Db/Db Mice. Int. J. Obes. 2020, 44, 1691– 1702,  DOI: 10.1038/s41366-020-0573-z
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    9
    Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice
    Wang, Hong; Kuusela, Sara; Rinnankoski-Tuikka, Rita; Dumont, Vincent; Bouslama, Rim; Ramadan, Usama Abo; Waaler, Jo; Linden, Anni-Maija; Chi, Nai-Wen; Krauss, Stefan; Pirinen, Eija; Lehtonen, Sanna
    International Journal of Obesity (2020), 44 (8), 1691-1702CODEN: IJOBDP; ISSN:0307-0565. (Nature Research)
    Abstr.: Objective: Human TNKS, encoding tankyrase 1 (TNKS1), localizes to a susceptibility locus for obesity and type 2 diabetes mellitus (T2DM). Here, we addressed the therapeutic potential of G007-LK, a TNKS-specific inhibitor, for obesity and T2DM. Methods: We administered G007-LK to diabetic db/db mice and measured the impact on body wt., abdominal adiposity, and serum metabolites. Muscle, liver, and white adipose tissues were analyzed by quant. RT-PCR and western blotting to det. TNKS inhibition, lipolysis, beiging, adiponectin level, mitochondrial oxidative metab. and mass, and gluconeogenesis. Protein interaction and PARylation analyses were carried out by immunopptn., pull-down and in situ proximity ligation assays. Results: TNKS inhibition reduced body wt. gain, abdominal fat content, serum cholesterol levels, steatosis, and proteins assocd. with lipolysis in diabetic db/db mice. We discovered that TNKS assocs. with PGC-1α and that TNKS inhibition attenuates PARylation of PGC-1α, contributing to increased PGC-1α level in WAT and muscle in db/db mice. PGC-1α upregulation apparently modulated transcriptional reprogramming to increase mitochondrial mass and fatty acid oxidative metab. in muscle, beiging of WAT, and raised circulating adiponectin level in db/db mice. This was in sharp contrast to the liver, where TNKS inhibition in db/db mice had no effect on PGC-1α expression, lipid metab., or gluconeogenesis. Conclusion: Our study unravels a novel mol. mechanism whereby pharmacol. inhibition of TNKS in obesity and diabetes enhances oxidative metab. and ameliorates lipid disorder. This happens via tissue-specific PGC-1α-driven transcriptional reprogramming in muscle and WAT, without affecting liver. This highlights inhibition of TNKS as a potential pharmacotherapy for obesity and T2DM.
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  10. 10
    Azarm, K.; Bhardwaj, A.; Kim, E.; Smith, S. Persistent Telomere Cohesion Protects Aged Cells from Premature Senescence. Nat. Commun. 2020, 11, 3321  DOI: 10.1038/s41467-020-17133-4
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    10
    Persistent telomere cohesion protects aged cells from premature senescence
    Azarm, Kameron; Bhardwaj, Amit; Kim, Eugenie; Smith, Susan
    Nature Communications (2020), 11 (1), 3321CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: Human telomeres are bound by the telomere repeat binding proteins TRF1 and TRF2. Telomere shortening in human cells leads to a DNA damage response that signals replicative senescence. While insufficient loading of TRF2 at shortened telomeres contributes to the DNA damage response in senescence, the contribution of TRF1 to senescence induction has not been detd. Here we show that counter to TRF2 deficiency-mediated induction of DNA damage, TRF1 deficiency serves a protective role to limit induction of DNA damage induced by subtelomere recombination. Shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion. Our findings suggest that the persistent cohesion protects short telomeres from inappropriate recombination. Ultimately, in the final division, telomeres are no longer able to maintain cohesion and subtelomere copying ensues. Thus, the gradual loss of TRF1 and concomitant persistent cohesion that occurs with telomere shortening ensures a measured approach to replicative senescence.
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  11. 11
    Li, N.; Zhang, Y.; Han, X.; Liang, K.; Wang, J.; Feng, L.; Wang, W.; Songyang, Z.; Lin, C.; Yang, L.; Yu, Y.; Chen, J. Poly-ADP Ribosylation of PTEN by Tankyrases Promotes PTEN Degradation and Tumor Growth. Genes Dev. 2015, 29, 157– 170,  DOI: 10.1101/gad.251785.114
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    11
    Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth
    Li Nan; Wang Jiadong; Feng Lin; Wang Wenqi; Chen Junjie; Zhang Yajie; Yu Yonghao; Han Xin; Liang Ke; Lin Chunru; Yang Liuqing; Songyang Zhou
    Genes & development (2015), 29 (2), 157-70 ISSN:.
    PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post-translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN-AKT pathway that can be explored further for cancer treatment.
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  12. 12
    Kim, S.; Han, S.; Kim, Y.; Kim, H.-S.; Gu, Y.-R.; Kang, D.; Cho, Y.; Kim, H.; Lee, J.; Seo, Y.; Chang, M. J.; Chang, C. B.; Kang, S.-B.; Kim, J.-H. Tankyrase Inhibition Preserves Osteoarthritic Cartilage by Coordinating Cartilage Matrix Anabolism via Effects on SOX9 PARylation. Nat. Commun. 2019, 10, 4898  DOI: 10.1038/s41467-019-12910-2
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    12
    Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation
    Kim Sukyeong; Han Sangbin; Kim Yeongjae; Kim Hyeon-Seop; Gu Young-Ran; Kang Donghyun; Cho Yongsik; Kim Hyeonkyeong; Lee Jeeyeon; Seo Yeyoung; Kim Jin-Hong; Kim Sukyeong; Han Sangbin; Kim Yeongjae; Kim Hyeon-Seop; Gu Young-Ran; Kang Donghyun; Cho Yongsik; Kim Hyeonkyeong; Lee Jeeyeon; Seo Yeyoung; Kim Jin-Hong; Chang Moon Jong; Kang Seung-Baik; Chang Chong Bum; Kim Jin-Hong
    Nature communications (2019), 10 (1), 4898 ISSN:.
    Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage.
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  13. 13
    Mukai, T.; Fujita, S.; Morita, Y. Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2. Cells 2019, 8, 195– 208,  DOI: 10.3390/cells8020195
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    13
    Tankyrase (PARP5) inhibition induces bone loss through accumulation of its substrate SH3BP2
    Mukai, Tomoyuki; Fujita, Shunichi; Morita, Yoshitaka
    Cells (2019), 8 (2), 195CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)
    There is considerable interest in tankyrase because of its potential use in cancer therapy. Tankyrase catalyzes the ADP-ribosylation of a variety of target proteins and regulates various cellular processes. The anti-cancer effects of tankyrase inhibitors are mainly due to their suppression of Wnt signaling and inhibition of telomerase activity, which are mediated by AXIN and TRF1 stabilization, resp. In this review, we describe the underappreciated effects of another substrate, SH3 domain-binding protein 2 (SH3BP2). Specifically, SH3BP2 is an adaptor protein that regulates intracellular signaling pathways. Addnl., in the human genetic disorder cherubism, the gain-of-function mutations in SH3BP2 enhance osteoclastogenesis. The pharmacol. inhibition of tankyrase in mice induces bone loss through the accumulation of SH3BP2 and the subsequent increase in osteoclast formation. These findings reveal the novel functions of tankyrase influencing bone homeostasis, and imply that tankyrase inhibitor treatments in a clin. setting may be assocd. with adverse effects on bone mass.
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  14. 14
    Peters, X. Q.; Malinga, T. H.; Agoni, C.; Olotu, F. A.; Soliman, M. E. S. Zoning in on Tankyrases: A Brief Review on the Past, Present and Prospective Studies. Anti-Cancer Agents Med. Chem. 2020, 19, 1920– 1934,  DOI: 10.2174/1871520619666191019114321
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  15. 15
    Zimmerlin, L.; Zambidis, E. T. Pleiotropic Roles of Tankyrase/PARP Proteins in the Establishment and Maintenance of Human Naïve Pluripotency. Exp. Cell Res. 2020, 390, 111935– 111945,  DOI: 10.1016/j.yexcr.2020.111935
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    15
    Pleiotropic roles of tankyrase/PARP proteins in the establishment and maintenance of human naive pluripotency
    Zimmerlin, Ludovic; Zambidis, Elias T.
    Experimental Cell Research (2020), 390 (1), 111935CODEN: ECREAL; ISSN:0014-4827. (Elsevier B.V.)
    Tankyrase 1 (TNKS1; PARP-5a) and Tankyrase 2 (TNKS2; PARP-5b) are poly-ADP-ribosyl-polymerase (PARP)-domain-contg. proteins that regulate the activities of a wide repertoire of target proteins via post-translational addn. of poly-ADP-ribose polymers (PARylation). Although tankyrases were first identified as regulators of human telomere elongation, important and expansive roles of tankyrase activity have recently emerged in the development and maintenance of stem cell states. Herein, we summarize the current state of knowledge of the various tankyrase-mediated activities that may promote human naive and 'extended' pluripotency'. We review the putative role of tankyrase and PARP inhibition in trophectoderm specification, telomere elongation, DNA repair and chromosomal segregation, metab., and PTEN-mediated apoptosis. Importantly, tankyrases possess PARP-independent activities that include regulation of MDC1-assocd. DNA repair by homologous recombination (HR) and autophagy/pexophagy, which is an essential mechanism of protein synthesis in the preimplantation embryo. Addnl., tankyrases auto-regulate themselves via auto-PARylation which augments their cellular protein levels and potentiates their non-PARP tankyrase functions. We propose that these non-PARP-related activities of tankyrase proteins may further independently affect both naive and extended pluripotency via mechanisms that remain undetd. We broadly outline a hypothetical framework for how inclusion of a tankyrase/PARP inhibitor in small mol. cocktails may stabilize and potentiate naive and extended pluripotency via pleiotropic routes and mechanisms.
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    Huang, S.-M. A.; Mishina, Y. M.; Liu, S.; Cheung, A.; Stegmeier, F.; Michaud, G. A.; Charlat, O.; Wiellette, E.; Zhang, Y.; Wiessner, S.; Hild, M.; Shi, X.; Wilson, C. J.; Mickanin, C.; Myer, V.; Fazal, A.; Tomlinson, R.; Serluca, F.; Shao, W.; Cheng, H.; Shultz, M.; Rau, C.; Schirle, M.; Schlegl, J.; Ghidelli, S.; Fawell, S.; Lu, C.; Curtis, D.; Kirschner, M. W.; Lengauer, C.; Finan, P. M.; Tallarico, J. A.; Bouwmeester, T.; Porter, J. A.; Bauer, A.; Cong, F. Tankyrase Inhibition Stabilizes Axin and Antagonizes Wnt Signalling. Nature 2009, 461, 614– 620,  DOI: 10.1038/nature08356
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    Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
    Huang, Shih-Min A.; Mishina, Yuji M.; Liu, Shanming; Cheung, Atwood; Stegmeier, Frank; Michaud, Gregory A.; Charlat, Olga; Wiellette, Elizabeth; Zhang, Yue; Wiessner, Stephanie; Hild, Marc; Shi, Xiaoying; Wilson, Christopher J.; Mickanin, Craig; Myer, Vic; Fazal, Aleem; Tomlinson, Ronald; Serluca, Fabrizio; Shao, Wenlin; Cheng, Hong; Shultz, Michael; Rau, Christina; Schirle, Markus; Schlegl, Judith; Ghidelli, Sonja; Fawell, Stephen; Lu, Chris; Curtis, Daniel; Kirschner, Marc W.; Lengauer, Christoph; Finan, Peter M.; Tallarico, John A.; Bouwmeester, Tewis; Porter, Jeffery A.; Bauer, Andreas; Cong, Feng
    Nature (London, United Kingdom) (2009), 461 (7264), 614-620CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The stability of the Wnt pathway transcription factor β-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited no. of pathway components that are amenable to small mol. inhibition. Here, we used a chem. genetic screen to identify a small mol., XAV939, which selectively inhibits β-catenin-mediated transcription. XAV939 stimulates β-catenin degrdn. by stabilizing axin, the concn.-limiting component of the destruction complex. Using a quant. chem. proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degrdn. through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.
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  17. 17
    Wang, Y.; Jiang, W.; Liu, X.; Zhang, Y. Tankyrase 2 (TNKS2) Polymorphism Associated with Risk in Developing Non-Small Cell Lung Cancer in a Chinese Population. Pathol., Res. Pract. 2015, 211, 766– 771,  DOI: 10.1016/j.prp.2015.07.003
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    Tankyrase 2 (TNKS2) polymorphism associated with risk in developing non-small cell lung cancer in a Chinese population
    Wang, Ying; Jiang, Weiyu; Liu, Xiaogu; Zhang, Yongjun
    Pathology, Research and Practice (2015), 211 (10), 766-771CODEN: PARPDS; ISSN:0344-0338. (Elsevier GmbH)
    We investigated the assocn. between poly(ADP-ribose) polymerase Tankyrase 2 (TNKS2) single-nucleotide polymorphisms (SNPs) and the risk of developing non-small cell lung cancer (NSCLC) in a Han Chinese population. Five-hundred NSCLC cases and 500 healthy controls were genotyped for four TNKS2 tagging SNPs (rs1538833, rs1538833, rs1340420, and rs1340420). The assocn. between genotype and NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) using multivariate unconditional logistic regression analyses. Individual alleles of the four TNKS2 SNPs were not assocd. with NSCLC risk in the studied Chinese population. However, patients carrying TNKS2 rs1340420 G/G and A/G genotypes were assocd. with a lower risk of developing NSCLC and adenocarcinoma (OR = 0.14; 95% CI = 0.02-1.15 and OR = 0.11; 95% CI = 0.03-0.91, resp.), whereas females patients homozygous for the TNKS2 rs1770474 T allele, a rare type, were assocd. with a higher risk of developing squamous-cell carcinoma (SCC) (OR = 4.67; 95% CI = 0.87-25.01). TNKS2 rs1340420 SNP was assocd. with lower NSCLC risk, whereas rs1770474 SNP was assocd. with higher SCC risk, suggesting that these two SNPs may be useful predictors of risk of developing NSCLC and SCC in this Chinese population.
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    Zamudio-Martinez, E.; Herrera-Campos, A. B.; Muñoz, A.; Rodríguez-Vargas, J. M.; Oliver, F. J. Tankyrases as Modulators of Pro-Tumoral Functions: Molecular Insights and Therapeutic Opportunities. J. Exp. Clin. Cancer Res. 2021, 40, 144  DOI: 10.1186/s13046-021-01950-6
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    Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities
    Zamudio-Martinez, Esteban; Herrera-Campos, Ana Belen; Munoz, Alberto; Rodriguez-Vargas, Jose Manuel; Oliver, F. Javier
    Journal of Experimental & Clinical Cancer Research (2021), 40 (1), 144CODEN: JECRDN; ISSN:1756-9966. (BioMed Central Ltd.)
    A review. Tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) are two homologous proteins that are gaining increasing importance due to their implication in multiple pathways and diseases such as cancer. TNKS1/2 interact with a large variety of substrates through the ankyrin (ANK) domain, which recognizes a sequence present in all the substrates of tankyrase, called Tankyrase Binding Motif (TBM). One of the main functions of tankyrases is the regulation of protein stability through the process of PARylation-dependent ubiquitination (PARdU). Nonetheless, there are other functions less studied that are also essential in order to understand the role of tankyrases in many pathways. In this , we conc. in different tankyrase substrates and we analyze in depth the biol. consequences derived of their interaction with TNKS1/2. We also examine the concept of both canonical and non-canonical TBMs and finally, we focus on the information about the role of TNKS1/2 in different tumor context, along with the benefits and limitations of the current TNKS inhibitors targeting the catalytic PARP domain and the novel strategies to develop inhibitors against the ankyrin domain. Available data indicates the need for further deepening in the knowledge of tankyrases to elucidate and improve the current view of the role of these PARP family members and get inhibitors with a better therapeutic and safety profile.
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    Liu, Z.; Wang, P.; Wold, E. A.; Song, Q.; Zhao, C.; Wang, C.; Zhou, J. Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer. J. Med. Chem. 2021, 64, 4257– 4288,  DOI: 10.1021/acs.jmedchem.0c01799
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    19
    Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer
    Liu, Zhiqing; Wang, Pingyuan; Wold, Eric A.; Song, Qiaoling; Zhao, Chenyang; Wang, Changyun; Zhou, Jia
    Journal of Medicinal Chemistry (2021), 64 (8), 4257-4288CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery. From the prodn. and secretion of WNT ligands, their binding to membrane receptors, and the β-catenin destruction complex to the expansive β-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling. Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clin. trials. Herein we summarize recent progress in the drug discovery and development of small-mol. inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochem. properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted.
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    Chen, B.; Dodge, M. E.; Tang, W.; Lu, J.; Ma, Z.; Fan, C.-W.; Wei, S.; Hao, W.; Kilgore, J.; Williams, N. S.; Roth, M. G.; Amatruda, J. F.; Chen, C.; Lum, L. Small Molecule–Mediated Disruption of Wnt-Dependent Signaling in Tissue Regeneration and Cancer. Nat. Chem. Biol. 2009, 5, 100– 107,  DOI: 10.1038/nchembio.137
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    Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer
    Chen, Baozhi; Dodge, Michael E.; Tang, Wei; Lu, Jianming; Ma, Zhiqiang; Fan, Chih-Wei; Wei, Shuguang; Hao, Wayne; Kilgore, Jessica; Williams, Noelle S.; Roth, Michael G.; Amatruda, James F.; Chen, Chuo; Lum, Lawrence
    Nature Chemical Biology (2009), 5 (2), 100-107CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
    The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small mols. that target Wnt-mediated cellular responses. By screening a diverse synthetic chem. library, we have discovered two new classes of small mols. that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the prodn. of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/β-catenin pathway activity. With these small mols., we establish a chem. genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/β-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chem. tractable addnl. contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chem. genetics and therapeutic goals.
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    Voronkov, A.; Holsworth, D. D.; Waaler, J.; Wilson, S. R.; Ekblad, B.; Perdreau-Dahl, H.; Dinh, H.; Drewes, G.; Hopf, C.; Morth, J. P.; Krauss, S. Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor. J. Med. Chem. 2013, 56, 3012– 3023,  DOI: 10.1021/jm4000566
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    Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor
    Voronkov, Andrew; Holsworth, Daniel D.; Waaler, Jo; Wilson, Steven R.; Ekblad, Bie; Perdreau-Dahl, Harmonie; Dinh, Huyen; Drewes, Gerard; Hopf, Carsten; Morth, Jens P.; Krauss, Stefan
    Journal of Medicinal Chemistry (2013), 56 (7), 3012-3023CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tankyrases 1 and 2 (TNKS1/2) are promising pharmacol. biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chem. analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochem. IC50 values of 46 nM and 25 nM, resp., and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystd. with 66, and the X-ray structure was detd. at 2.8 Å resoln. in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compd.'s high target selectivity and specificity. Our study provides a significantly optimized compd. for targeting TNKS1/2 in vitro and in vivo.
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    Bregman, H.; Chakka, N.; Guzman-Perez, A.; Gunaydin, H.; Gu, Y.; Huang, X.; Berry, V.; Liu, J.; Teffera, Y.; Huang, L.; Egge, B.; Mullady, E. L.; Schneider, S.; Andrews, P. S.; Mishra, A.; Newcomb, J.; Serafino, R.; Strathdee, C. A.; Turci, S. M.; Wilson, C.; DiMauro, E. F. Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors. J. Med. Chem. 2013, 56, 4320– 4342,  DOI: 10.1021/jm4000038
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    22
    Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
    Bregman, Howard; Chakka, Nagasree; Guzman-Perez, Angel; Gunaydin, Hakan; Gu, Yan; Huang, Xin; Berry, Virginia; Liu, Jingzhou; Teffera, Yohannes; Huang, Liyue; Egge, Bryan; Mullady, Erin L.; Schneider, Steve; Andrews, Paul S.; Mishra, Ankita; Newcomb, John; Serafino, Randy; Strathdee, Craig A.; Turci, Susan M.; Wilson, Cindy; DiMauro, Erin F.
    Journal of Medicinal Chemistry (2013), 56 (11), 4320-4342CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concns., resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compd. I is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and mol. modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (II, III).
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    Hua, Z.; Bregman, H.; Buchanan, J. L.; Chakka, N.; Guzman-Perez, A.; Gunaydin, H.; Huang, X.; Gu, Y.; Berry, V.; Liu, J.; Teffera, Y.; Huang, L.; Egge, B.; Emkey, R.; Mullady, E. L.; Schneider, S.; Andrews, P. S.; Acquaviva, L.; Dovey, J.; Mishra, A.; Newcomb, J.; Saffran, D.; Serafino, R.; Strathdee, C. A.; Turci, S. M.; Stanton, M.; Wilson, C.; DiMauro, E. F. Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors. J. Med. Chem. 2013, 56, 10003– 10015,  DOI: 10.1021/jm401317z
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    Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
    Hua, Zihao; Bregman, Howard; Buchanan, John L.; Chakka, Nagasree; Guzman-Perez, Angel; Gunaydin, Hakan; Huang, Xin; Gu, Yan; Berry, Virginia; Liu, Jingzhou; Teffera, Yohannes; Huang, Liyue; Egge, Bryan; Emkey, Renee; Mullady, Erin L.; Schneider, Steve; Andrews, Paul S.; Acquaviva, Lisa; Dovey, Jennifer; Mishra, Ankita; Newcomb, John; Saffran, Douglas; Serafino, Randy; Strathdee, Craig A.; Turci, Susan M.; Stanton, Mary; Wilson, Cindy; DiMauro, Erin F.
    Journal of Medicinal Chemistry (2013), 56 (24), 10003-10015CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which neg. regulate the Wnt pathway by promoting β-catenin degrdn. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compd. N-(2-methoxyphenyl)-4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)propanamido)benzamide was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compd. collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein the authors report the structure- and property-based optimization of N-(2-methoxyphenyl)-4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)propanamido)benzamide leading to the identification of more potent and selective tankyrase inhibitors with improved pharmacokinetic properties in rodents, which are well suited as tool compds. for further in vivo validation studies.
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    McGonigle, S.; Chen, Z.; Wu, J.; Chang, P.; Kolber-Simonds, D.; Ackermann, K.; Twine, N. C.; Shie, J.; Miu, J. T.; Huang, K.-C.; Moniz, G. A.; Nomoto, K. E7449: A Dual Inhibitor of PARP1/2 and Tankyrase1/2 Inhibits Growth of DNA Repair Deficient Tumors and Antagonizes Wnt Signaling. Oncotarget 2015, 6, 41307– 41323,  DOI: 10.18632/oncotarget.5846
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    24
    E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling
    McGonigle Sharon; Chen Zhihong; Wu Jiayi; Kolber-Simonds Donna; Ackermann Karen; Twine Natalie C; Shie Jue-Lon; Miu Jingzang Tao; Huang Kuan-Chun; Nomoto Kenichi; Chang Paul; Chang Paul; Miu Jingzang Tao; Moniz George A; Moniz George A
    Oncotarget (2015), 6 (38), 41307-23 ISSN:.
    Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.
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    Paine, H. A.; Nathubhai, A.; Woon, E. C. Y.; Sunderland, P. T.; Wood, P. J.; Mahon, M. F.; Lloyd, M. D.; Thompson, A. S.; Haikarainen, T.; Narwal, M.; Lehtiö, L.; Threadgill, M. D. Exploration of the Nicotinamide-Binding Site of the Tankyrases, Identifying 3-Arylisoquinolin-1-Ones as Potent and Selective Inhibitors in Vitro. Bioorg. Med. Chem. 2015, 23, 5891– 5908,  DOI: 10.1016/j.bmc.2015.06.061
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    25
    Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro
    Paine, Helen A.; Nathubhai, Amit; Woon, Esther C. Y.; Sunderland, Peter T.; Wood, Pauline J.; Mahon, Mary F.; Lloyd, Matthew D.; Thompson, Andrew S.; Haikarainen, Teemu; Narwal, Mohit; Lehtio, Lari; Threadgill, Michael D.
    Bioorganic & Medicinal Chemistry (2015), 23 (17), 5891-5908CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signaling). Using mol. modeling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesized by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, redn. and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Me and methoxy were optimal at the 5-position. SAR was rationalized by modeling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.
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    Nkizinkiko, Y.; Suneel Kumar, B. V. S.; Jeankumar, V. U.; Haikarainen, T.; Koivunen, J.; Madhuri, C.; Yogeeswari, P.; Venkannagari, H.; Obaji, E.; Pihlajaniemi, T.; Sriram, D.; Lehtiö, L. Discovery of Potent and Selective Nonplanar Tankyrase Inhibiting Nicotinamide Mimics. Bioorg. Med. Chem. 2015, 23, 4139– 4149,  DOI: 10.1016/j.bmc.2015.06.063
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    Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics
    Nkizinkiko, Yves; Suneel Kumar, B. V. S.; Jeankumar, Variam Ullas; Haikarainen, Teemu; Koivunen, Jarkko; Madhuri, Chanduri; Yogeeswari, Perumal; Venkannagari, Harikanth; Obaji, Ezeogo; Pihlajaniemi, Taina; Sriram, Dharmarajan; Lehtio, Lari
    Bioorganic & Medicinal Chemistry (2015), 23 (15), 4139-4149CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Diphtheria toxin-like ADP-ribosyltransferases catalyze a posttranslational modification, ADP-ribosylation and form a protein family of 17 members in humans. Two of the family members, tankyrases 1 and 2, are involved in several cellular processes including mitosis and Wnt/β-catenin signaling pathway. They are often over-expressed in cancer cells and have been linked with the survival of cancer cells making them potential therapeutic targets. In this study, the authors identified nine tankyrase inhibitors through virtual and in vitro screening. Crystal structures of tankyrase 2 with the compds. showed that they bind to the nicotinamide binding site of the catalytic domain. Based on the co-crystal structures the authors designed and synthesized a series of tetrahydroquinazolin-4-one and pyridopyrimidin-4-one analogs and were subsequently able to improve the potency of a hit compd. almost 100-fold (from 11 μM to 150 nM). The most potent compds. were selective towards tankyrases over a panel of other human ARTD enzymes. They also inhibited Wnt/β-catenin pathway in a cell-based reporter assay demonstrating the potential usefulness of the identified new scaffolds for further development.
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  27. 27
    Haikarainen, T.; Waaler, J.; Ignatev, A.; Nkizinkiko, Y.; Venkannagari, H.; Obaji, E.; Krauss, S.; Lehtiö, L. Development and Structural Analysis of Adenosine Site Binding Tankyrase Inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 328– 333,  DOI: 10.1016/j.bmcl.2015.12.018
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    27
    Development and structural analysis of adenosine site binding tankyrase inhibitors
    Haikarainen, Teemu; Waaler, Jo; Ignatev, Alexander; Nkizinkiko, Yves; Venkannagari, Harikanth; Obaji, Ezeogo; Krauss, Stefan; Lehtio, Lari
    Bioorganic & Medicinal Chemistry Letters (2016), 26 (2), 328-333CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compds. against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compds. in complex with tankyrase 2. The compds. bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chem. modifications of the compds. The structural anal. allows further rational development of this compd. class as a potent and selective tankyrase inhibitor.
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  28. 28
    Anumala, U. R.; Waaler, J.; Nkizinkiko, Y.; Ignatev, A.; Lazarow, K.; Lindemann, P.; Olsen, P. A.; Murthy, S.; Obaji, E.; Majouga, A. G.; Leonov, S.; von Kries, J. P.; Lehtiö, L.; Krauss, S.; Nazaré, M. Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach. J. Med. Chem. 2017, 60, 10013– 10025,  DOI: 10.1021/acs.jmedchem.7b00883
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    Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
    Anumala, Upendra Rao; Waaler, Jo; Nkizinkiko, Yves; Ignatev, Alexander; Lazarow, Katina; Lindemann, Peter; Olsen, Petter Angell; Murthy, Sudarshan; Obaji, Ezeogo; Majouga, Alexander G.; Leonov, Sergey; von Kries, Jens Peter; Lehtioe, Lari; Krauss, Stefan; Nazare, Marc
    Journal of Medicinal Chemistry (2017), 60 (24), 10013-10025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 (1-(trans-3-(4-(2-Chlorophenyl)-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydro-2-oxo-1H-benzimidazole-5-carbonitrile) displays high target affinity on tankyrase 1 and 2 with biochem. and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, resp., and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Crit. for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and Ph linker.
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  29. 29
    Ferri, M.; Liscio, P.; Carotti, A.; Asciutti, S.; Sardella, R.; Macchiarulo, A.; Camaioni, E. Targeting Wnt-Driven Cancers: Discovery of Novel Tankyrase Inhibitors. Eur. J. Med. Chem. 2017, 142, 506– 522,  DOI: 10.1016/j.ejmech.2017.09.030
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    29
    Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors
    Ferri, Martina; Liscio, Paride; Carotti, Andrea; Asciutti, Stefania; Sardella, Roccaldo; Macchiarulo, Antonio; Camaioni, Emidio
    European Journal of Medicinal Chemistry (2017), 142 (), 506-522CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A review. Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the mol. interactions with the target, the authors discuss only those ones acting against Wnt cancer cell lines. In addn., comprehensive structure property relationships (SPR) emerging from the hit evolution processes and preclin. results are provided. The authors then review the most promising TNKSi hitherto reported in literature, acting in vivo models of Wnt-driven cancers. Some out-looks on current issues and future directions in this field are also discussed.
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  30. 30
    Di Micco, S.; Pulvirenti, L.; Bruno, I.; Terracciano, S.; Russo, A.; Vaccaro, M. C.; Ruggiero, D.; Muccilli, V.; Cardullo, N.; Tringali, C.; Riccio, R.; Bifulco, G. Identification by Inverse Virtual Screening of Magnolol-Based Scaffold as New Tankyrase-2 Inhibitors. Bioorg. Med. Chem. 2018, 26, 3953– 3957,  DOI: 10.1016/j.bmc.2018.06.019
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    30
    Identification by Inverse Virtual Screening of magnolol-based scaffold as new tankyrase-2 inhibitors
    Di Micco, Simone; Pulvirenti, Luana; Bruno, Ines; Terracciano, Stefania; Russo, Alessandra; Vaccaro, Maria C.; Ruggiero, Dafne; Muccilli, Vera; Cardullo, Nunzio; Tringali, Corrado; Riccio, Raffaele; Bifulco, Giuseppe
    Bioorganic & Medicinal Chemistry (2018), 26 (14), 3953-3957CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    The natural product magnolol (1) and a selection of its bioinspired derivs. 2-5, were investigated by Inverse Virtual Screening in order to identify putative biol. targets from a panel of 308 proteins involved in cancer processes. By this in silico anal. we selected tankyrase-2 (TNKS2), casein kinase 2 (CK2) and bromodomain 9 (Brd9) as potential targets for exptl. evaluations. The Surface Plasmon Resonance assay revealed that 3-5 present a good affinity for tankyrase-2, and, in particular, 3 showed an antiproliferative activity on A549 cells higher than the well-known tankyrase-2 inhibitor XAV939 used as ref. compd.
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  31. 31
    Mizutani, A.; Yashiroda, Y.; Muramatsu, Y.; Yoshida, H.; Chikada, T.; Tsumura, T.; Okue, M.; Shirai, F.; Fukami, T.; Yoshida, M.; Seimiya, H. RK-287107, a Potent and Specific Tankyrase Inhibitor, Blocks Colorectal Cancer Cell Growth in a Preclinical Model. Cancer Sci. 2018, 109, 4003– 4014,  DOI: 10.1111/cas.13805
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    RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model
    Mizutani, Anna; Yashiroda, Yoko; Muramatsu, Yukiko; Yoshida, Haruka; Chikada, Tsubasa; Tsumura, Takeshi; Okue, Masayuki; Shirai, Fumiyuki; Fukami, Takehiro; Yoshida, Minoru; Seimiya, Hiroyuki
    Cancer Science (2018), 109 (12), 4003-4014CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)
    Tankyrase poly(ADP-ribosyl)ates (PARylates) Axin, a neg. regulator of β-catenin. This post-translational modification causes ubiquitin-dependent degrdn. of Axin, resulting in β-catenin accumulation. Tankyrase inhibitors downregulate β-catenin and suppress the growth of APC-mutated colorectal cancer cells. Herein, we report a novel tankyrase-specific inhibitor RK-287107, which inhibits tankyrase-1 and -2 four- and eight-fold more potently, resp., than G007-LK, a tankyrase inhibitor that has been previously reported as effective in mouse xenograft models. RK-287107 causes Axin2 accumulation and downregulates β-catenin, T-cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated APC mutations. Consistently, RK-287107 inhibits the growth of APC-mutated (β-catenin-dependent) colorectal cancer COLO-320DM and SW403 cells but not the APC-wild (β-catenin-independent) colorectal cancer RKO cells. I.p. or oral administration of RK-287107 suppresses COLO-320DM tumor growth in NOD-SCID mice. Rates of tumor growth inhibition showed good correlation with the behavior of pharmacodynamic biomarkers, such as Axin2 accumulation and MYC downregulation. These observations indicate that RK-287107 exerts a proof-of-concept antitumor effect, and thus may have potential for tankyrase-directed mol. cancer therapy.
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  32. 32
    Menon, M.; Elliott, R.; Bowers, L.; Balan, N.; Rafiq, R.; Costa-Cabral, S.; Munkonge, F.; Trinidade, I.; Porter, R.; Campbell, A. D.; Johnson, E. R.; Esdar, C.; Buchstaller, H.-P.; Leuthner, B.; Rohdich, F.; Schneider, R.; Sansom, O.; Wienke, D.; Ashworth, A.; Lord, C. J. A Novel Tankyrase Inhibitor, MSC2504877, Enhances the Effects of Clinical CDK4/6 Inhibitors. Sci. Rep. 2019, 9, 201216  DOI: 10.1038/s41598-018-36447-4
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    Shirai, F.; Tsumura, T.; Yashiroda, Y.; Yuki, H.; Niwa, H.; Sato, S.; Chikada, T.; Koda, Y.; Washizuka, K.; Yoshimoto, N.; Abe, M.; Onuki, T.; Mazaki, Y.; Hirama, C.; Fukami, T.; Watanabe, H.; Honma, T.; Umehara, T.; Shirouzu, M.; Okue, M.; Kano, Y.; Watanabe, T.; Kitamura, K.; Shitara, E.; Muramatsu, Y.; Yoshida, H.; Mizutani, A.; Seimiya, H.; Yoshida, M.; Koyama, H. Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors. J. Med. Chem. 2019, 62, 3407– 3427,  DOI: 10.1021/acs.jmedchem.8b01888
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    Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors
    Shirai, Fumiyuki; Tsumura, Takeshi; Yashiroda, Yoko; Yuki, Hitomi; Niwa, Hideaki; Sato, Shin; Chikada, Tsubasa; Koda, Yasuko; Washizuka, Kenichi; Yoshimoto, Nobuko; Abe, Masako; Onuki, Tetsuo; Mazaki, Yui; Hirama, Chizuko; Fukami, Takehiro; Watanabe, Hirofumi; Honma, Teruki; Umehara, Takashi; Shirouzu, Mikako; Okue, Masayuki; Kano, Yuko; Watanabe, Takashi; Kitamura, Kouichi; Shitara, Eiki; Muramatsu, Yukiko; Yoshida, Haruka; Mizutani, Anna; Seimiya, Hiroyuki; Yoshida, Minoru; Koyama, Hiroo
    Journal of Medicinal Chemistry (2019), 62 (7), 3407-3427CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin signal by preventing poly ADP-ribosylation dependent degrdn. of AXIN, a neg. regulator of Wnt/β-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small mol. inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a(I), a high-throughput screening hit, the spiroindoline deriv. 40c(II) (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7,000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. II also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that II is a promising lead compd. for the development of novel tankyrase inhibitors as anticancer agents.
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    Buchstaller, H.-P.; Anlauf, U.; Dorsch, D.; Kuhn, D.; Lehmann, M.; Leuthner, B.; Musil, D.; Radtki, D.; Ritzert, C.; Rohdich, F.; Schneider, R.; Esdar, C. Discovery and Optimization of 2-Arylquinazolin-4-Ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity. J. Med. Chem. 2019, 62, 7897– 7909,  DOI: 10.1021/acs.jmedchem.9b00656
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    Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity
    Buchstaller, Hans-Peter; Anlauf, Uwe; Dorsch, Dieter; Kuhn, Daniel; Lehmann, Martin; Leuthner, Birgitta; Musil, Djordje; Radtki, Daniela; Ritzert, Claudio; Rohdich, Felix; Schneider, Richard; Esdar, Christina
    Journal of Medicinal Chemistry (2019), 62 (17), 7897-7909CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tankyrases 1 and 2 (TNKS1/2) are promising pharmacol. targets which recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the Ph residue. These efforts were supported by anal. of TNKS X-ray and Watermap structures and resulted in compd. 5k(I), a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of I in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compd. in a colorectal xenograft model in vivo.
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    Sabnis, R. W. Novel 4-Heteroarylcarbonyl-N-(Phenyl or Heteroaryl) Piperidine-1-Carboxamides as Tankyrase Inhibitors. ACS Med. Chem. Lett. 2020, 11, 1676– 1677,  DOI: 10.1021/acsmedchemlett.0c00390
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    35
    Novel 4-Heteroarylcarbonyl-N-(phenyl or heteroaryl) Piperidine-1-carboxamides as Tankyrase Inhibitors
    Sabnis, Ram W.
    ACS Medicinal Chemistry Letters (2020), 11 (9), 1676-1677CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    There is no expanded citation for this reference.
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  36. 36
    Kinosada, H.; Okada-Iwasaki, R.; Kunieda, K.; Suzuki-Imaizumi, M.; Takahashi, Y.; Miyagi, H.; Suzuki, M.; Motosawa, K.; Watanabe, M.; Mie, M.; Ishii, T.; Ishida, H.; Saito, J.-I.; Nakai, R. The Dual Pocket Binding Novel Tankyrase Inhibitor K-476 Enhances the Efficacy of Immune Checkpoint Inhibitor by Attracting CD8+ T Cells to Tumors. Am. J. Cancer Res. 2021, 11, 264– 276
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    The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8+ T cells to tumors
    Kinosada, Haruka; Okada-Iwasaki, Ryoko; Kunieda, Kana; Suzuki-Imaizumi, Minami; Takahashi, Yuichi; Miyagi, Hikaru; Suzuki, Michihiko; Motosawa, Keiichi; Watanabe, Miwa; Mie, Motoya; Ishii, Toshihiko; Ishida, Hiroshi; Saito, Jun-ichi; Nakai, Ryuichiro
    American Journal of Cancer Research (2021), 11 (1), 264-276CODEN: AJCRFT; ISSN:2156-6976. (e-Century Publishing Corp.)
    The Wnt/β-catenin pathway, which is assocd. with disease progression, is activated in many cancers. Tankyrase (TNKS) has received attention as a target mol. for Wnt/β-catenin pathway inhibition. We identified K-476, a novel TNKS inhibitor, a dual pocket binder that binds to both the nicotinamide and ADP-ribose pockets. In a human colon cancer cell line, K-476 specifically and potently inhibited TNKS and led to stabilization of the Axin protein, resulting in Wnt/β-catenin pathway suppression. Aberrant Wnt/β-catenin pathway activation was recently reported as a possible mechanism of ineffectiveness in immune checkpoint inhibitor (ICI) treatment. Because the Wnt/β-catenin pathway activation causes dendritic cell inactivation and suppresses chemokine prodn., resulting in a paucity of CD8+ T cells in tumor tissue, which is an important effector of ICIs. Thus, TNKS inhibitors may enhance the efficacy of ICIs. To examine whether K-476 enhances the antitumor effect of anti-PD-L1 antibodies, K-476 was administered orally with an anti-PD-L1 antibody to melanoma-bearing C57BL/6J mice. Although K-476 was ineffective as a monotherapy, it significantly enhanced the antitumor effect in combination with anti-PD-L1 antibody. In mice, intra-tumor infiltration of CD8+ T cells was increased by combination treatment. K-476 upregulated the chemokine expression (e.g., Ccl3 and Ccl4), which attracted CD8+ T cells. This was considered to contribute to the increased CD8+ T cells in the tumor microenvironment. Furthermore, while the potential gastrointestinal toxicity of TNKS inhibitors has been reported, it was not obsd. at EDs. Thus, K-476 could be an attractive therapeutic option to enhance the efficacy of ICIs.
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    Mehta, C. C.; Bhatt, H. G. Tankyrase Inhibitors as Antitumor Agents: A Patent Update (2013 – 2020). Expert Opin. Ther. Pat. 2021, 31, 645– 661,  DOI: 10.1080/13543776.2021.1888929
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    Tankyrase inhibitors as antitumor agents: a patent update (2013 - 2020)
    Mehta, Chirag C.; Bhatt, Hardik G.
    Expert Opinion on Therapeutic Patents (2021), 31 (7), 645-661CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
    IntroductionTankyrase inhibitors gained significant attention as therapeutic targets in oncol. because of their potency. Their primary role in inhibiting the Wnt signaling pathway makes them an important class of compds. with the potential to be used as a combination therapy in future treatments of colorectal cancer. Areas coveredThis review describes pertinent work in the development of tankyrase inhibitors with a great emphasis on the recently patented TNKS inhibitors published from 2013 to 2020. This article also highlights a couple of promising candidates having tankyrase inhibitory effects and are currently undergoing clin. trials. Expert opinionFollowing the successful clin. applications of PARP inhibitors, tankyrase inhibition has gained significant attention in the research community as a target with high therapeutic potential. The ubiquitous role of tankyrase in cellular homeostasis and Wnt-dependent tumor proliferation brought difficulties for researchers to strike the right balance between potency and on-target toxicity. The need for novel tankyrase inhibitors with a better ADMET profile can introduce an addnl. regimen in treating various malignancies in monotherapy or adjuvant therapy. The development of combination therapies, including tankyrase inhibitors with or without PARP inhibitory properties, can potentially benefit the larger population of patients with unmet medical needs.
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  38. 38
    Waaler, J.; Machon, O.; Kries, J. P.; von Wilson, S. R.; Lundenes, E.; Wedlich, D.; Gradl, D.; Paulsen, J. E.; Machonova, O.; Dembinski, J. L.; Dinh, H.; Krauss, S. Novel Synthetic Antagonists of Canonical Wnt Signaling Inhibit Colorectal Cancer Cell Growth. Cancer Res. 2011, 71, 197– 205,  DOI: 10.1158/0008-5472.CAN-10-1282
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    Novel Synthetic Antagonists of Canonical Wnt Signaling Inhibit Colorectal Cancer Cell Growth
    Waaler, Jo; Machon, Ondrej; von Kries, Jens Peter; Wilson, Steven Ray; Lundenes, Elsa; Wedlich, Doris; Gradl, Dietmar; Paulsen, Jan Erik; Machonova, Olga; Dembinski, Jennifer L.; Dinh, Huyen; Krauss, Stefan
    Cancer Research (2011), 71 (1), 197-205CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role in tumor cell growth and progression. Here we report the identification of 2 new small mols. that specifically inhibit canonical Wnt pathway at the level of the destruction complex. Specificity was verified in various cellular reporter systems, a Xenopus double-axis formation assay and a gene expression profile anal. In human colorectal cancer (CRC) cells, the new compds. JW67 and JW74 rapidly reduced active β-catenin with a subsequent downregulation of Wnt target genes, including AXIN2, SP5, and NKD1. Notably, AXIN2 protein levels were strongly increased after compd. exposure. Long-term treatment with JW74 inhibited the growth of tumor cells in both a mouse xenograft model of CRC and in ApcMin mice (multiple intestinal neoplasia, Min). Our findings rationalize further preclin. and clin. evaluation of these new compds. as novel modalities for cancer treatment. Cancer Res; 71(1); 197-205.
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  39. 39
    Waaler, J.; Leenders, R. G. G.; Sowa, S. T.; Alam Brinch, S.; Lycke, M.; Nieczypor, P.; Aertssen, S.; Murthy, S.; Galera-Prat, A.; Damen, E.; Wegert, A.; Nazaré, M.; Lehtiö, L.; Krauss, S. Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor. J. Med. Chem. 2020, 63, 6834– 6846,  DOI: 10.1021/acs.jmedchem.0c00208
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    Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor
    Waaler, Jo; Leenders, Ruben G. G.; Sowa, Sven T.; Alam Brinch, Shoshy; Lycke, Max; Nieczypor, Piotr; Aertssen, Sjoerd; Murthy, Sudarshan; Galera-Prat, Albert; Damen, Eddy; Wegert, Anita; Nazare, Marc; Lehtio, Lari; Krauss, Stefan
    Journal of Medicinal Chemistry (2020), 63 (13), 6834-6846CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compd. 1 (I) were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compds. reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 (II) resolves previous atropisomerism, soly., and Caco-2 efflux liabilities. 13 Shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.
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    Zhong, Y.; Katavolos, P.; Nguyen, T.; Lau, T.; Boggs, J.; Sambrone, A.; Kan, D.; Merchant, M.; Harstad, E.; Diaz, D.; Costa, M.; Schutten, M. Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index <1. Toxicol. Pathol. 2016, 44, 267– 278,  DOI: 10.1177/0192623315621192
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    Tankyrase inhibition causes reversible intestinal toxicity in mice with a therapeutic index < 1
    Zhong, Yu; Katavolos, Paula; Nguyen, Trung; Lau, Ted; Boggs, Jason; Sambrone, Amy; Kan, David; Merchant, Mark; Harstad, Eric; Diaz, Dolores; Costa, Mike; Schutten, Melissa
    Toxicologic Pathology (2016), 44 (2), 267-278CODEN: TOPADD; ISSN:0192-6233. (Sage Publications)
    Activated Wnt/β-catenin signaling is frequently assocd. with colorectal cancer. Wnt inhibitors, including tankyrase inhibitors, are being explored as potential anticancer agents. Wnt signaling is also crit. for intestinal tissue homeostasis, and Wnt inhibitors have been shown to cause intestinal toxicity in mice by affecting intestinal stem cells. This study sought to characterize the intestinal toxicity of tankyrase inhibitors, including reversibility, and to assess their therapeutic index. Novel tankyrase inhibitor G-631 caused dose-dependent intestinal toxicity with a therapeutic index < 1 after 14 days of dosing in mice. At a tolerated subtherapeutic dose level, the intestinal toxicity was composed of enteritis characterized by villus blunting, epithelial degeneration, and inflammation, which fully reversed after 14 days of recovery. Doubled exposure showed weak antitumor activity in a xenograft colorectal cancer model but also caused more severe intestinal toxicity characterized by multifocal-regionally extensive necrotizing and ulcerative enteritis leading to morbidity or moribundity in some animals. This toxicity was only partially reversed after 14 days of recovery, with evidence of crypt and villus regeneration, mildly blunted villi, and/or scarring in assocn. with chronic inflammation of the submucosa. Therefore, the clin. utility of tankyrase inhibitors is likely limited by the on-target intestinal toxicity and a therapeutic index < 1 in mice.
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  41. 41
    Qin, D.; Lin, X.; Liu, Z.; Chen, Y.; Zhang, Z.; Wu, C.; Liu, L.; Pan, Y.; Laquerre, S.; Emery, J.; Fergusson, J.; Roland, K.; Keenan, R.; Oliff, A.; Kumar, S.; Cheung, M.; Su, D.-S. Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors. ACS Med. Chem. Lett. 2021, 12, 1005– 1010,  DOI: 10.1021/acsmedchemlett.1c00160
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    41
    Discovery of Orally Bioavailable Ligand Efficient Quinazolinediones as Potent and Selective Tankyrases Inhibitors
    Qin, Donghui; Lin, Xiaojuan; Liu, Zhi; Chen, Yan; Zhang, Zhiliu; Wu, Chengde; Liu, Linlin; Pan, Yan; Laquerre, Sylvie; Emery, John; Fergusson, Jeff; Roland, Kimberly; Keenan, Rick; Oliff, Allen; Kumar, Sanjay; Cheung, Mui; Su, Dai-Shi
    ACS Medicinal Chemistry Letters (2021), 12 (6), 1005-1010CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    The authors report the discovery of quinazolinediones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compd. I (R1 = R2 = R3 = H, R4 = NHCH2Ph), led to truncated analogs, e.g., I (R1 = H, F, Cl, OMe, Me, R2 = H, F, Me, CONH2, R3 = H, CF3, Me, Cl, R4 = OH, 4-pyridylamino, 1-methyl-4-pyrazolylamino, etc.), that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compd. I (R1 = R2 = H, R3 = CF3, R4 = OH) (II) exhibited excellent potencies in cells and proliferation studies, good selectivity, in vitro activities, and an excellent PK profile. Compd. II also inhibited H292 xenograft tumor growth in nude mice. The synthesis, biol., pharmacokinetic, in vivo efficacy studies, and safety profiles of compds. are presented.
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  42. 42
    Kwak, Y. H.; Barrientos, T.; Furman, B.; Zhang, H.; Puviindran, V.; Cutcliffe, H.; Herfarth, J.; Nwankwo, E.; Alman, B. A. Pharmacologic Targeting of β-Catenin Improves Fracture Healing in Old Mice. Sci. Rep. 2019, 9, 9005  DOI: 10.1038/s41598-019-45339-0
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    Pharmacologic targeting of β-catenin improves fracture healing in old mice
    Kwak Yoon Hae; Barrientos Tomasa; Furman Bridgette; Zhang Hazel; Puviindran Vijitha; Cutcliffe Hattie; Herfarth Jonas; Nwankwo Eugene; Alman Benjamin A; Kwak Yoon Hae; Alman Benjamin A
    Scientific reports (2019), 9 (1), 9005 ISSN:.
    β-catenin protein needs to be precisely regulated for effective fracture repair. The pace of fracture healing slows with age, associated with a transient increase in β-catenin during the initial phase of the repair process. Here we examined the ability of pharmacologic agents that target β-catenin to improve the quality of fracture repair in old mice. 20 month old mice were treated with Nefopam or the tankyrase inhibitor XAV939 after a tibia fracture. Fractures were examined 21 days later by micro-CT and histology, and 28 days later using mechanical testing. Daily treatment with Nefopam for three or seven days but not ten days improved the amount of bone present at the fracture site, inhibited β-catenin protein level, and increased colony forming units osteoblastic from bone marrow cells. At 28 days, treatment increased the work to fracture of the injured tibia. XAV939 had a more modest effect on β-catenin protein, colony forming units osteoblastic, and the amount of bone at the fracture site. This data supports the notion that high levels of β-catenin in the early phase of fracture healing in old animals slows osteogenesis, and suggests a pharmacologic approach that targets β-catenin to improve fracture repair in the elderly.
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  43. 43
    Zhong, L.; Ding, Y.; Bandyopadhyay, G.; Waaler, J.; Börgeson, E.; Smith, S.; Zhang, M.; Phillips, S. A.; Mahooti, S.; Mahata, S. K.; Shao, J.; Krauss, S.; Chi, N.-W. The PARsylation Activity of Tankyrase in Adipose Tissue Modulates Systemic Glucose Metabolism in Mice. Diabetologia 2016, 59, 582– 591,  DOI: 10.1007/s00125-015-3815-1
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    43
    The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice
    Zhong, Linlin; Ding, Yun; Bandyopadhyay, Gautam; Waaler, Jo; Borgeson, Emma; Smith, Susan; Zhang, Mingchen; Phillips, Susan A.; Mahooti, Sepi; Mahata, Sushil K.; Shao, Jianhua; Krauss, Stefan; Chi, Nai-Wen
    Diabetologia (2016), 59 (3), 582-591CODEN: DBTGAJ; ISSN:0012-186X. (Springer)
    Aims/hypothesis: Tankyrase (TNKS) is a ubiquitously expressed mol. scaffold that is implicated in diverse processes. The catalytic activity of TNKS modifies substrate proteins through poly-ADP-ribosylation (PARsylation) and is responsive to cellular energetic state. Global deficiency of the TNKS protein in mice accelerates glucose utilization and raises plasma adiponectin levels. The aim of this study was to investigate whether the PARsylation activity of TNKS in adipocytes plays a role in systemic glucose homeostasis. Methods: To inhibit TNKS-mediated PARsylation, we fed mice with a diet contg. the TNKS-specific inhibitor G007-LK. To genetically inactivate TNKS catalysis in adipocytes while preserving its function as a mol. scaffold, we used an adipocyte-selective Cre transgene to delete TNKS exons that encoded the catalytic domain at the C-terminus. Tissue-specific insulin sensitivity in mice was investigated using hyperinsulinemic-euglycemic clamps. To model adipose-liver crosstalk ex vivo, we applied adipocyte-conditioned media to hepatocytes and assessed the effect on gluconeogenesis. Results: The TNKS inhibitor G007-LK improved glucose tolerance and insulin sensitivity and promptly increased plasma adiponectin levels. In female mice, but not in male mice, adipocyte-selective genetic inactivation of TNKS catalysis improved hepatic insulin sensitivity and post-transcriptionally increased plasma adiponectin levels. Both pharmacol. and genetic TNKS inhibition in female mouse-derived adipocytes induced a change in secreted factors to decrease gluconeogenesis in primary hepatocytes. Conclusions/interpretation: Systemic glucose homeostasis is regulated by the PARsylation activity of TNKS in adipocytes. This regulation is mediated in part by adipocyte-secreted factors that modulate hepatic glucose prodn. Pharmacol. TNKS inhibition could potentially be used to improve glucose tolerance.
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  44. 44
    Plummer, R.; Dua, D.; Cresti, N.; Drew, Y.; Stephens, P.; Foegh, M.; Knudsen, S.; Sachdev, P.; Mistry, B. M.; Dixit, V.; McGonigle, S.; Hall, N.; Matijevic, M.; McGrath, S.; Sarker, D. First-in-Human Study of the PARP/Tankyrase Inhibitor E7449 in Patients with Advanced Solid Tumours and Evaluation of a Novel Drug-Response Predictor. Br. J. Cancer 2020, 123, 525– 533,  DOI: 10.1038/s41416-020-0916-5
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    First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor
    Plummer, Ruth; Dua, Divyanshu; Cresti, Nicola; Drew, Yvette; Stephens, Peter; Foegh, Marie; Knudsen, Steen; Sachdev, Pallavi; Mistry, Bipin M.; Dixit, Vaishali; McGonigle, Sharon; Hall, Nancy; Matijevic, Mark; McGrath, Shannon; Sarker, Debashis
    British Journal of Cancer (2020), 123 (4), 525-533CODEN: BJCAAI; ISSN:0007-0920. (Nature Research)
    This phase 1 study examd. the safety, max.-tolerated dose (MTD) and antitumor activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumors (50-800-mg doses). Archival tumor samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumor types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumor activity in solid tumors, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 wk) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumor activity and significant concn.-dependent PARP inhibition following 50-800-mg oral dosing. The results support further clin. investigation of E7449 and its assocd. biomarker 2X-121 DRP.
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    Clinical-Trials-Registry/NCT01618136 and NCT04505839.
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    Pereira, J. A.; Pessoa, A. M.; Cordeiro, M. N. D. S.; Fernandes, R.; Prudêncio, C.; Noronha, J. P.; Vieira, M. Quinoxaline, Its Derivatives and Applications: A State of the Art Review. Eur. J. Med. Chem. 2015, 97, 664– 672,  DOI: 10.1016/j.ejmech.2014.06.058
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    Quinoxaline, its derivatives and applications: A State of the Art review
    Pereira, Joana A.; Pessoa, Ana M.; Cordeiro, M. Natalia D. S.; Fernandes, Ruben; Prudencio, Cristina; Noronha, Joao Paulo; Vieira, Monica
    European Journal of Medicinal Chemistry (2015), 97 (), 664-672CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
    A review. Quinoxaline derivs. are an important class of heterocycle compds., where N replaces some carbon atoms in the ring of naphthalene. Its mol. formula is C8H6N2, formed by the fusion of two arom. rings, benzene and pyrazine. It is rare in natural state, but their synthesis is easy to perform. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the quinoxaline and quinoxaline derivs., assocd. medical and biomedical value as well as industrial value. Modifying quinoxaline structure it is possible to obtain a wide variety of biomedical applications, namely antimicrobial activities and chronic and metabolic diseases treatment.
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    Baumeister, S.; Schepmann, D.; Wünsch, B. Synthesis and Receptor Binding of Thiophene Bioisosteres of Potent GluN2B Ligands with a Benzo[7]Annulene-Scaffold. Med. Chem. Commun. 2019, 10, 315– 325,  DOI: 10.1039/C8MD00545A
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    Quinn, L. A.; Moore, G. E.; Morgan, R. T.; Woods, L. K. Cell Lines from Human Colon Carcinoma with Unusual Cell Products, Double Minutes, and Homogeneously Staining Regions. Cancer Res. 1979, 39, 4914– 4924
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    Cell lines from human colon carcinoma with unusual cell products, double minutes, and homogeneously staining regions
    Quinn L A; Moore G E; Morgan R T; Woods L K
    Cancer research (1979), 39 (12), 4914-24 ISSN:0008-5472.
    Two human colon carcinoma cell lines derived from the same tumor specimen were characterized. The cell lines, COLO 320 and COLO 321, have amine precursor uptake and decarboxylation cell properties, such as ectopic production of norepinephrine, epinephrine, serotonin, adrenocorticotropic hormone, and parathyroid hormone. The cells were morphologically different from most colon cell lines. Double minutes (DM) were initially present in nearly 100% of the metaphases. In a few subcultures of COLO 320, DM have persisted for 1.5 years. However, in COLO 321 and some subcultures of COLO 320, a loss of DM was observed and new marker chromosomes with homogeneously staining regions were observed. These unusual cell lines should be valuable for studies of apudomas of the colon and the cytogenetic phenomena of DM and homogeneously staining regions.
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  49. 49
    Lau, T.; Chan, E.; Callow, M.; Waaler, J.; Boggs, J.; Blake, R. A.; Magnuson, S.; Sambrone, A.; Schutten, M.; Firestein, R.; Machon, O.; Korinek, V.; Choo, E.; Diaz, D.; Merchant, M.; Polakis, P.; Holsworth, D. D.; Krauss, S.; Costa, M. A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation–Driven Colorectal Tumor Growth. Cancer Res. 2013, 73, 3132– 3144,  DOI: 10.1158/0008-5472.CAN-12-4562
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    49
    A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation-Driven Colorectal Tumor Growth
    Lau, Ted; Chan, Emily; Callow, Marinella; Waaler, Jo; Boggs, Jason; Blake, Robert A.; Magnuson, Steven; Sambrone, Amy; Schutten, Melissa; Firestein, Ron; Machon, Ondrej; Korinek, Vladimir; Choo, Edna; Diaz, Dolores; Merchant, Mark; Polakis, Paul; Holsworth, Daniel D.; Krauss, Stefan; Costa, Mike
    Cancer Research (2013), 73 (10), 3132-3144CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/P-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-mol. tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt./p-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degrdn., thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approx. 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compd. G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity assocd. with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.
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  50. 50
    Solberg, N. T.; Waaler, J.; Lund, K.; Mygland, L.; Olsen, P. A.; Krauss, S. TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer. Mol Cancer Res. 2018, 16, 543– 553,  DOI: 10.1158/1541-7786.MCR-17-0362
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    TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer
    Solberg, Nina T.; Waaler, Jo; Lund, Kaja; Mygland, Line; Olsen, Petter A.; Krauss, Stefan
    Molecular Cancer Research (2018), 16 (3), 543-553CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)
    Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clin. practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond pos. to TNKS inhibition in vitro and in vivo. Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor-sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/β-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts in vivo. At the highest doses, tumor xenograft growth was halted without affecting the body wt. of the tested animals. Implications: Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. Mol Cancer Res; 16(3); 543-53. ©2017 AACR.
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    Waaler, J.; Machon, O.; Tumova, L.; Dinh, H.; Korinek, V.; Wilson, S. R.; Paulsen, J. E.; Pedersen, N. M.; Eide, T. J.; Machonova, O.; Gradl, D.; Voronkov, A.; Kries, J. P.; von Krauss, S. A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice. Cancer Res. 2012, 72, 2822– 2832,  DOI: 10.1158/0008-5472.CAN-11-3336
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    A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice
    Waaler, Jo; Machon, Ondrej; Tumova, Lucie; Dinh, Huyen; Korinek, Vladimir; Wilson, Steven Ray; Paulsen, Jan Erik; Pedersen, Nina Marie; Eide, Tor J.; Machonova, Olga; Gradl, Dietmar; Voronkov, Andrey; von Kries, Jens Peter; Krauss, Stefan
    Cancer Research (2012), 72 (11), 2822-2832CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    This preclin. proof-of-concept study suggests a new strategy to treat colon cancer by increasing the degrdn. of β-catenin, which drives this disease.
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    WO2019243822A1.
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    Narwal, M.; Fallarero, A.; Vuorela, P.; Lehtiö, L. Homogeneous Screening Assay for Human Tankyrase. J. Biomol. Screen 2012, 17, 593– 604,  DOI: 10.1177/1087057112436558
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    Homogeneous screening assay for human tankyrase
    Narwal, Mohit; Fallarero, Adyary; Vuorela, Pia; Lehtio, Lari
    Journal of Biomolecular Screening (2012), 17 (5), 593-604CODEN: JBISF3; ISSN:1087-0571. (Sage Publications)
    Tankyrase, a member of human PARP protein super-family, catalyzes a covalent post-translational modification of substrate proteins. This modification, poly(ADP-ribos)ylation, leads to changes in protein interactions and modifies downstream signaling events. Tankyrase 1 is a potential drug target due to its functions in telomere homeostasis and in Wnt signaling. We describe here optimization and application of an activity-based homogenous assay for tankyrase inhibitors in a high-throughput screening format. The method measures the consumption of substrate by the chem. conversion of the remaining NAD+ into a stable fluorescent condensation product. Conditions were optimized to measure the enzymic auto-modification of a recombinant catalytic fragment of tankyrase 1. The fluorescence assay is inexpensive, operationally easy and performs well according to the statistical anal. (Z'= 0.7). A validatory screen with a natural product library confirmed suitability of the assay for finding new tankyrase inhibitors. Flavone was the most potent (IC50=325 nM) hit from the natural compds. A flavone deriv., apigenin, and iso-Pr gallate showed potency on the micromolar range, but displayed over 30-fold selectivity for tankyrase over the studied isoenzymes PARP1 and PARP2. The assay is robust and will be useful for screening new tankyrase inhibitors.
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    Kabsch, W. XDS. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 125– 132,  DOI: 10.1107/S0907444909047337
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    Software XDS for image rotation, recognition and crystal symmetry assignment
    Kabsch, Wolfgang
    Acta Crystallographica, Section D: Biological Crystallography (2010), 66 (2), 125-132CODEN: ABCRE6; ISSN:0907-4449. (International Union of Crystallography)
    The usage and control of recent modifications of the program package XDS for the processing of rotation images are described in the context of previous versions. New features include automatic detn. of spot size and reflecting range and recognition and assignment of crystal symmetry. Moreover, the limitations of earlier package versions on the no. of correction/scaling factors and the representation of pixel contents have been removed. Large program parts have been restructured for parallel processing so that the quality and completeness of collected data can be assessed soon after measurement.
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    McCoy, A. J.; Grosse-Kunstleve, R. W.; Adams, P. D.; Winn, M. D.; Storoni, L. C.; Read, R. J. Phaser Crystallographic Software. J. Appl. Crystallogr. 2007, 40, 658– 674,  DOI: 10.1107/S0021889807021206
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    Phaser crystallographic software
    McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.; Winn, Martyn D.; Storoni, Laurent C.; Read, Randy J.
    Journal of Applied Crystallography (2007), 40 (4), 658-674CODEN: JACGAR; ISSN:0021-8898. (International Union of Crystallography)
    Phaser is a program for phasing macromol. crystal structures by both mol. replacement and exptl. phasing methods. The novel phasing algorithms implemented in Phaser have been developed using max. likelihood and multivariate statistics. For mol. replacement, the new algorithms have proved to be significantly better than traditional methods in discriminating correct solns. from noise, and for single-wavelength anomalous dispersion exptl. phasing, the new algorithms, which account for correlations between F+ and F-, give better phases (lower mean phase error with respect to the phases given by the refined structure) than those that use mean F and anomalous differences ΔF. One of the design concepts of Phaser was that it be capable of a high degree of automation. To this end, Phaser (written in C++) can be called directly from Python, although it can also be called using traditional CCP4 keyword-style input. Phaser is a platform for future development of improved phasing methods and their release, including source code, to the crystallog. community.
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    Emsley, P.; Cowtan, K. Coot: Model-Building Tools for Molecular Graphics. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 2126– 2132,  DOI: 10.1107/S0907444904019158
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    Coot: model-building tools for molecular graphics
    Emsley, Paul; Cowtan, Kevin
    Acta Crystallographica, Section D: Biological Crystallography (2004), D60 (12, Pt. 1), 2126-2132CODEN: ABCRE6; ISSN:0907-4449. (Blackwell Publishing Ltd.)
    CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for x-ray structure soln., structure comparison and anal., and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as 'Coot'.
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    Murshudov, G. N.; Skubák, P.; Lebedev, A. A.; Pannu, N. S.; Steiner, R. A.; Nicholls, R. A.; Winn, M. D.; Long, F.; Vagin, A. A. REFMAC5 for the Refinement of Macromolecular Crystal Structures. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2011, 67, 355– 367,  DOI: 10.1107/S0907444911001314
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    57
    REFMAC5 for the refinement of macromolecular crystal structures
    Murshudov, Garib N.; Skubak, Pavol; Lebedev, Andrey A.; Pannu, Navraj S.; Steiner, Roberto A.; Nicholls, Robert A.; Winn, Martyn D.; Long, Fei; Vagin, Alexei A.
    Acta Crystallographica, Section D: Biological Crystallography (2011), 67 (4), 355-367CODEN: ABCRE6; ISSN:0907-4449. (International Union of Crystallography)
    This paper describes various components of the macromol. crystallog. refinement program REFMAC5, which is distributed as part of the CCP4 suite. REFMAC5 utilizes different likelihood functions depending on the diffraction data employed (amplitudes or intensities), the presence of twinning and the availability of SAD/SIRAS exptl. diffraction data. To ensure chem. and structural integrity of the refined model, REFMAC5 offers several classes of restraints and choices of model parameterization. Reliable models at resolns. at least as low as 4 Å can be achieved thanks to low-resoln. refinement tools such as secondary-structure restraints, restraints to known homologous structures, automatic global and local NCS restraints, 'jelly-body' restraints and the use of novel long-range restraints on at. displacement parameters (ADPs) based on the Kullback-Leibler divergence. REFMAC5 addnl. offers TLS parameterization and, when high-resoln. data are available, fast refinement of anisotropic ADPs. Refinement in the presence of twinning is performed in a fully automated fashion. REFMAC5 is a flexible and highly optimized refinement package that is ideally suited for refinement across the entire resoln. spectrum encountered in macromol. crystallog.
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  1. Sudarshan Murthy, Maria Giulia Nizi, Mirko M. Maksimainen, Serena Massari, Juho Alaviuhkola, Barbara E. Lippok, Chiara Vagaggini, Sven T. Sowa, Albert Galera-Prat, Yashwanth Ashok, Harikanth Venkannagari, Renata Prunskaite-Hyyryläinen, Elena Dreassi, Bernhard Lüscher, Patricia Korn, Oriana Tabarrini, Lari Lehtiö. [1,2,4]Triazolo[3,4-b]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes. Journal of Medicinal Chemistry 2023, 66 (2) , 1301-1320. https://doi.org/10.1021/acs.jmedchem.2c01460
  2. Maria Giulia Nizi, Mirko M. Maksimainen, Lari Lehtiö, Oriana Tabarrini. Medicinal Chemistry Perspective on Targeting Mono-ADP-Ribosylating PARPs with Small Molecules. Journal of Medicinal Chemistry 2022, 65 (11) , 7532-7560. https://doi.org/10.1021/acs.jmedchem.2c00281
  3. Mingfeng Yu, Yuchao Yang, Matthew Sykes, Shudong Wang. Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer. Journal of Medicinal Chemistry 2022, 65 (7) , 5244-5273. https://doi.org/10.1021/acs.jmedchem.1c02139
  4. Xiaopeng Peng, Wanyi Pan, Feng Jiang, Weiming Chen, Zetao Qi, Weijie Peng, Jianjun Chen. Selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors for cancer therapy. Pharmacological Research 2022, 186 , 106529. https://doi.org/10.1016/j.phrs.2022.106529
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  • Abstract

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    Figure 1

    Figure 1. Lead compound 1 (OM-1700) and main modifications.

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    Figure 2

    Figure 2. Short list of six compounds and 1 including their respective biochemical TNKS2 and cellular (HEK293) WNT/β-catenin signaling reporter assays IC50 values in nM. clog P and tPSA (in Å2) as calculated by DataWarrior v5.5.0. Moieties in color were different from 1.

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    Figure 3

    Figure 3. Co-crystal structure of TNKS2 with 24 (PDB 7O6X). The protein is shown in blue, and 24 in green. The dashed lines in black represent hydrogen bonds, and the red spheres represent water molecules. The σA weighted 2Fo – Fc electron density maps around the ligands are contoured at 1.8σ.

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    Figure 4

    Figure 4. Compound 24 decreased cell growth and inhibited WNT/β-catenin signaling activity in COLO 320DM cells. (a) 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) colorimetric cell growth assay for various doses of 24 in APCmutated COLO 320DM (black) and APCwild-type RKO (gray) cells. After 5 days, the antiproliferative effect of compound treatment was measured at 490 nm. Mean value ± standard deviation (SD) for one representative experiment of more than three repeated assays, each with six replicates, are shown. Dotted lines depict 50% (GI50-value) and 25% (GI25-value) growth inhibition levels and control = 100% (0.1% dimethyl sulfoxide (DMSO)). (b) Representative immunoblots of cytoplasmic TNKS1/2, AXIN1, AXIN2, and cytoplasmic and nuclear transcriptionally active β-catenin (non-phospho) and β-catenin. Actin and lamin B1 show equal protein loading, while # indicates that the same actin immunoblot is used as loading control for both AXIN2 and β-catenin. For (b) and (c), control = 0.001% DMSO. (c) Real-time RT-qPCR analyses of WNT/β-catenin signaling target genes (AXIN2, DKK1, NKD1, and APCDD1). Boxplots show median, first and third quartiles, and maximum and minimum whiskers for combined data from three independent experiments with three replicates each. Dotted lines depict the control mean value = 1. For (a) and (c), analysis of variance (ANOVA) tests (Holm–Sidak method, versus control) are indicated by *** (p < 0.001) and * (p < 0.05), while ANOVA on ranks tests (Dunn’s method, versus control) are indicated by † (p < 0.05).

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  • References

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    This article references 57 other publications.

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      Canonical Wnt signaling is controlled intracellularly by the level of β-catenin protein, which is dependent on Axin scaffolding of a complex that phosphorylates β-catenin to target it for ubiquitylation and proteasomal degrdn. This function of Axin is counteracted through relocalization of Axin protein to the Wnt receptor complex to allow for ligand-activated Wnt signaling. AXIN1 and AXIN2 protein levels are regulated by tankyrase-mediated poly(ADP-ribosyl)ation (PARsylation), which destabilizes Axin and promotes signaling. Mechanistically, how tankyrase limits Axin protein accumulation, and how tankyrase levels and activity are regulated for this function, are currently under investigation. By RNAi screening, we identified the RNF146 RING-type ubiquitin E3 ligase as a pos. regulator of Wnt signaling that operates with tankyrase to maintain low steady-state levels of Axin proteins. RNF146 also destabilizes tankyrases TNKS1 and TNKS2 proteins and, in a reciprocal relationship, tankyrase activity reduces RNF146 protein levels. We show that RNF146, tankyrase, and Axin form a protein complex, and that RNF146 mediates ubiquitylation of all 3 proteins to target them for proteasomal degrdn. RNF146 is a cytoplasmic protein that also prevents tankyrase protein aggregation at a centrosomal location. Tankyrase auto-PARsylation and PARsylation of Axin is known to lead to proteasome-mediated degrdn. of these proteins, and we demonstrate that, through ubiquitylation, RNF146 mediates this process to regulate Wnt signaling.
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      A review. Several cellular signaling pathways are regulated by ADP-ribosylation, a posttranslational modification catalyzed by members of the ARTD superfamily. Tankyrases are distinguishable from the rest of this family by their unique domain organization, notably the sterile alpha motif responsible for oligomerization and ankyrin repeats mediating protein-protein interactions. Tankyrases are involved in various cellular functions, such as telomere homeostasis, Wnt/β -catenin signaling, glucose metab., and cell cycle progression. In these processes, Tankyrases regulate the interactions and stability of target proteins by poly (ADP-ribosyl)ation. Modified proteins are subsequently recognized by the E3 ubiquitin ligase RNF146, poly-ubiquitinated and predominantly guided to 26S proteasomal degrdn. Several small mol. inhibitors have been described for Tankyrases; they compete with the co-substrate NAD+ for binding to the ARTD catalytic domain. The recent, highly potent and selective inhibitors possess several properties of lead compds. and can be used for proof-of-concept studies in cancer and other Tankyrase linked diseases.
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      Specific E3 ligases target tumor suppressors for degrdation. Inhibition of such E3 ligases may be an important approach to cancer treatment. RNF146 is a RING domain and PARylation-dependent E3 ligase that functions as an activator of the β-catenin/Wnt and YAP/Hippo pathways by targeting the degrdation of several tumor suppressors. Tankyrases 1 and 2 (TNKS1/2) are the only known poly-ADP-ribosyltransferases that require RNF146 to degrade their substrates. However, systematic identification of RNF146 substrates have not yet been performed. To uncover substrates of RNF146 that are targeted for degrdation, we generated RNF146 knockout cells and TNKS1/2-double knockout cells and performed proteome profiling with label-free quantification as well as transcriptome anal. We identified 160 potential substrates of RNF146, which included many known substrates of RNF146 and TNKS1/2 and 122 potential TNKS-independent substrates of RNF146. In addn., we validated OTU domain-contg. protein 5 and Protein mono-ADP-ribosyltransferase PARP10 as TNKS1/2-independent substrates of RNF146 and SARDH as a novel substrate of TNKS1/2 and RNF146. Our study is the first proteome-wide anal. of potential RNF146 substrates. Together, these findings not only demonstrate that proteome profiling can be a useful general approach for the systemic identification of substrates of E3 ligases but also reveal new substrates of RNF146, which provides a resource for further functional studies.
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      Tankyrase 1, a human telomeric poly(ADP-ribose) polymerase, was originally identified through its interaction with TRF1, a neg. regulator of telomere length. Tankyrase 1 ADP-ribosylates TRF1 in vitro, and its over-expression induces telomere elongation in human cancer cells. In addn. to its telomeric localization, tankyrase 1 resides at multiple subcellular sites, suggesting addnl. functions for this protein. Here the authors identify TAB182, a novel tankyrase 1-binding protein of 182 kDa. TAB182 displays a complex pattern of subcellular localization. TAB182 localizes to the nucleus in a heterochromatic staining pattern and to the cytoplasm, where it co-stains with the cortical actin network. TAB182 coimmunoppts. with tankyrase 1 from human cells and serves as an acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in vitro. Like TRF1, TAB182 binds to the ankyrin domain (comprising 24 ankyrin repeats) of tankyrase 1. Surprisingly, dissection of this domain reveals multiple discrete and overlapping binding sites for TRF1 and TAB182. Thus, the authors demonstrate five well conserved ankyrin repeat clusters in tankyrase 1. Although each of the five ankyrin repeat clusters independently binds to TRF1, only three of the five bind to TAB182. These findings suggest that tankyrase 1 may act as a scaffold for large mol. mass complexes made up of multiple binding proteins. The authors discuss potential roles for tankyrase 1-mediated higher order complexes at telomeres and at other subcellular sites.
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      The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymg. TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochem. studies informed by these structures demonstrate that polymn. is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling.
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      Pollock, K.; Liu, M.; Zaleska, M.; Meniconi, M.; Pfuhl, M.; Collins, I.; Guettler, S. Fragment-Based Screening Identifies Molecules Targeting the Substrate-Binding Ankyrin Repeat Domains of Tankyrase. Sci. Rep. 2019, 9, 19130  DOI: 10.1038/s41598-019-55240-5
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      Scientific Reports (2019), 9 (1), 19130CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      The PARP enzyme and scaffolding protein tankyrase (TNKS, TNKS2) uses its ankyrin repeat clusters (ARCs) to bind a wide range of proteins and thereby controls diverse cellular functions. A no. of these are implicated in cancer-relevant processes, including Wnt/β-catenin signaling, Hippo signaling and telomere maintenance. The ARCs recognize a conserved tankyrase-binding peptide motif (TBM). All currently available tankyrase inhibitors target the catalytic domain and inhibit tankyrase's poly(ADP-ribosyl)ation function. However, there is emerging evidence that catalysis-independent "scaffolding" mechanisms contribute to tankyrase function. Here we report a fragment-based screening program against tankyrase ARC domains, using a combination of biophys. assays, including differential scanning fluorimetry (DSF) and NMR (NMR) spectroscopy. We identify fragment mols. that will serve as starting points for the development of tankyrase substrate binding antagonists. Such compds. will enable probing the scaffolding functions of tankyrase, and may, in the future, provide potential alternative therapeutic approaches to inhibiting tankyrase activity in cancer and other conditions.
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      Perdreau-Dahl, H.; Progida, C.; Barfeld, S. J.; Guldsten, H.; Thiede, B.; Arntzen, M.; Bakke, O.; Mills, I. G.; Krauss, S.; Morth, J. P. Sjögren Syndrome/Scleroderma Autoantigen 1 Is a Direct Tankyrase Binding Partner in Cancer Cells. Commun. Biol. 2020, 3, 123  DOI: 10.1038/s42003-020-0851-2
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      Sjogren syndrome/scleroderma autoantigen 1 is a direct Tankyrase binding partner in cancer cells
      Perdreau-Dahl Harmonie; Guldsten Hanne; Morth J Preben; Perdreau-Dahl Harmonie; Morth J Preben; Progida Cinzia; Bakke Oddmund; Barfeld Stefan J; Mills Ian G; Thiede Bernd; Arntzen Magnus; Mills Ian G; Mills Ian G; Krauss Stefan; Morth J Preben
      Communications biology (2020), 3 (1), 123 ISSN:.
      Sjogren syndrome/scleroderma autoantigen 1 (SSSCA1) was first described as an auto-antigen over-expressed in Sjogren's syndrome and in scleroderma patients. SSSCA1 has been linked to mitosis and centromere association and as a potential marker candidate in diverse solid cancers. Here we characterize SSSCA1 for the first time, to our knowledge, at the molecular, structural and subcellular level. We have determined the crystal structure of a zinc finger fold, a zinc ribbon domain type 2 (ZNRD2), at 2.3 ÅA resolution. We show that the C-terminal domain serves a dual function as it both behaves as the interaction site to Tankyrase 1 (TNKS1) and as a nuclear export signal. We identify TNKS1 as a direct binding partner of SSSCA1, map the binding site to TNKS1 ankyrin repeat cluster 2 (ARC2) and thus define a new binding sequence. We experimentally verify and map a new nuclear export signal sequence in SSSCA1.
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    9. 9
      Wang, H.; Kuusela, S.; Rinnankoski-Tuikka, R.; Dumont, V.; Bouslama, R.; Ramadan, U. A.; Waaler, J.; Linden, A.-M.; Chi, N.-W.; Krauss, S.; Pirinen, E.; Lehtonen, S. Tankyrase Inhibition Ameliorates Lipid Disorder via Suppression of PGC-1α PARylation in Db/Db Mice. Int. J. Obes. 2020, 44, 1691– 1702,  DOI: 10.1038/s41366-020-0573-z
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      Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice
      Wang, Hong; Kuusela, Sara; Rinnankoski-Tuikka, Rita; Dumont, Vincent; Bouslama, Rim; Ramadan, Usama Abo; Waaler, Jo; Linden, Anni-Maija; Chi, Nai-Wen; Krauss, Stefan; Pirinen, Eija; Lehtonen, Sanna
      International Journal of Obesity (2020), 44 (8), 1691-1702CODEN: IJOBDP; ISSN:0307-0565. (Nature Research)
      Abstr.: Objective: Human TNKS, encoding tankyrase 1 (TNKS1), localizes to a susceptibility locus for obesity and type 2 diabetes mellitus (T2DM). Here, we addressed the therapeutic potential of G007-LK, a TNKS-specific inhibitor, for obesity and T2DM. Methods: We administered G007-LK to diabetic db/db mice and measured the impact on body wt., abdominal adiposity, and serum metabolites. Muscle, liver, and white adipose tissues were analyzed by quant. RT-PCR and western blotting to det. TNKS inhibition, lipolysis, beiging, adiponectin level, mitochondrial oxidative metab. and mass, and gluconeogenesis. Protein interaction and PARylation analyses were carried out by immunopptn., pull-down and in situ proximity ligation assays. Results: TNKS inhibition reduced body wt. gain, abdominal fat content, serum cholesterol levels, steatosis, and proteins assocd. with lipolysis in diabetic db/db mice. We discovered that TNKS assocs. with PGC-1α and that TNKS inhibition attenuates PARylation of PGC-1α, contributing to increased PGC-1α level in WAT and muscle in db/db mice. PGC-1α upregulation apparently modulated transcriptional reprogramming to increase mitochondrial mass and fatty acid oxidative metab. in muscle, beiging of WAT, and raised circulating adiponectin level in db/db mice. This was in sharp contrast to the liver, where TNKS inhibition in db/db mice had no effect on PGC-1α expression, lipid metab., or gluconeogenesis. Conclusion: Our study unravels a novel mol. mechanism whereby pharmacol. inhibition of TNKS in obesity and diabetes enhances oxidative metab. and ameliorates lipid disorder. This happens via tissue-specific PGC-1α-driven transcriptional reprogramming in muscle and WAT, without affecting liver. This highlights inhibition of TNKS as a potential pharmacotherapy for obesity and T2DM.
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      Azarm, K.; Bhardwaj, A.; Kim, E.; Smith, S. Persistent Telomere Cohesion Protects Aged Cells from Premature Senescence. Nat. Commun. 2020, 11, 3321  DOI: 10.1038/s41467-020-17133-4
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      Persistent telomere cohesion protects aged cells from premature senescence
      Azarm, Kameron; Bhardwaj, Amit; Kim, Eugenie; Smith, Susan
      Nature Communications (2020), 11 (1), 3321CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: Human telomeres are bound by the telomere repeat binding proteins TRF1 and TRF2. Telomere shortening in human cells leads to a DNA damage response that signals replicative senescence. While insufficient loading of TRF2 at shortened telomeres contributes to the DNA damage response in senescence, the contribution of TRF1 to senescence induction has not been detd. Here we show that counter to TRF2 deficiency-mediated induction of DNA damage, TRF1 deficiency serves a protective role to limit induction of DNA damage induced by subtelomere recombination. Shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion. Our findings suggest that the persistent cohesion protects short telomeres from inappropriate recombination. Ultimately, in the final division, telomeres are no longer able to maintain cohesion and subtelomere copying ensues. Thus, the gradual loss of TRF1 and concomitant persistent cohesion that occurs with telomere shortening ensures a measured approach to replicative senescence.
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    11. 11
      Li, N.; Zhang, Y.; Han, X.; Liang, K.; Wang, J.; Feng, L.; Wang, W.; Songyang, Z.; Lin, C.; Yang, L.; Yu, Y.; Chen, J. Poly-ADP Ribosylation of PTEN by Tankyrases Promotes PTEN Degradation and Tumor Growth. Genes Dev. 2015, 29, 157– 170,  DOI: 10.1101/gad.251785.114
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      Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth
      Li Nan; Wang Jiadong; Feng Lin; Wang Wenqi; Chen Junjie; Zhang Yajie; Yu Yonghao; Han Xin; Liang Ke; Lin Chunru; Yang Liuqing; Songyang Zhou
      Genes & development (2015), 29 (2), 157-70 ISSN:.
      PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post-translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN-AKT pathway that can be explored further for cancer treatment.
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    12. 12
      Kim, S.; Han, S.; Kim, Y.; Kim, H.-S.; Gu, Y.-R.; Kang, D.; Cho, Y.; Kim, H.; Lee, J.; Seo, Y.; Chang, M. J.; Chang, C. B.; Kang, S.-B.; Kim, J.-H. Tankyrase Inhibition Preserves Osteoarthritic Cartilage by Coordinating Cartilage Matrix Anabolism via Effects on SOX9 PARylation. Nat. Commun. 2019, 10, 4898  DOI: 10.1038/s41467-019-12910-2
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      Tankyrase inhibition preserves osteoarthritic cartilage by coordinating cartilage matrix anabolism via effects on SOX9 PARylation
      Kim Sukyeong; Han Sangbin; Kim Yeongjae; Kim Hyeon-Seop; Gu Young-Ran; Kang Donghyun; Cho Yongsik; Kim Hyeonkyeong; Lee Jeeyeon; Seo Yeyoung; Kim Jin-Hong; Kim Sukyeong; Han Sangbin; Kim Yeongjae; Kim Hyeon-Seop; Gu Young-Ran; Kang Donghyun; Cho Yongsik; Kim Hyeonkyeong; Lee Jeeyeon; Seo Yeyoung; Kim Jin-Hong; Chang Moon Jong; Kang Seung-Baik; Chang Chong Bum; Kim Jin-Hong
      Nature communications (2019), 10 (1), 4898 ISSN:.
      Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage.
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    13. 13
      Mukai, T.; Fujita, S.; Morita, Y. Tankyrase (PARP5) Inhibition Induces Bone Loss through Accumulation of Its Substrate SH3BP2. Cells 2019, 8, 195– 208,  DOI: 10.3390/cells8020195
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      Tankyrase (PARP5) inhibition induces bone loss through accumulation of its substrate SH3BP2
      Mukai, Tomoyuki; Fujita, Shunichi; Morita, Yoshitaka
      Cells (2019), 8 (2), 195CODEN: CELLC6; ISSN:2073-4409. (MDPI AG)
      There is considerable interest in tankyrase because of its potential use in cancer therapy. Tankyrase catalyzes the ADP-ribosylation of a variety of target proteins and regulates various cellular processes. The anti-cancer effects of tankyrase inhibitors are mainly due to their suppression of Wnt signaling and inhibition of telomerase activity, which are mediated by AXIN and TRF1 stabilization, resp. In this review, we describe the underappreciated effects of another substrate, SH3 domain-binding protein 2 (SH3BP2). Specifically, SH3BP2 is an adaptor protein that regulates intracellular signaling pathways. Addnl., in the human genetic disorder cherubism, the gain-of-function mutations in SH3BP2 enhance osteoclastogenesis. The pharmacol. inhibition of tankyrase in mice induces bone loss through the accumulation of SH3BP2 and the subsequent increase in osteoclast formation. These findings reveal the novel functions of tankyrase influencing bone homeostasis, and imply that tankyrase inhibitor treatments in a clin. setting may be assocd. with adverse effects on bone mass.
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    14. 14
      Peters, X. Q.; Malinga, T. H.; Agoni, C.; Olotu, F. A.; Soliman, M. E. S. Zoning in on Tankyrases: A Brief Review on the Past, Present and Prospective Studies. Anti-Cancer Agents Med. Chem. 2020, 19, 1920– 1934,  DOI: 10.2174/1871520619666191019114321
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    15. 15
      Zimmerlin, L.; Zambidis, E. T. Pleiotropic Roles of Tankyrase/PARP Proteins in the Establishment and Maintenance of Human Naïve Pluripotency. Exp. Cell Res. 2020, 390, 111935– 111945,  DOI: 10.1016/j.yexcr.2020.111935
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      Pleiotropic roles of tankyrase/PARP proteins in the establishment and maintenance of human naive pluripotency
      Zimmerlin, Ludovic; Zambidis, Elias T.
      Experimental Cell Research (2020), 390 (1), 111935CODEN: ECREAL; ISSN:0014-4827. (Elsevier B.V.)
      Tankyrase 1 (TNKS1; PARP-5a) and Tankyrase 2 (TNKS2; PARP-5b) are poly-ADP-ribosyl-polymerase (PARP)-domain-contg. proteins that regulate the activities of a wide repertoire of target proteins via post-translational addn. of poly-ADP-ribose polymers (PARylation). Although tankyrases were first identified as regulators of human telomere elongation, important and expansive roles of tankyrase activity have recently emerged in the development and maintenance of stem cell states. Herein, we summarize the current state of knowledge of the various tankyrase-mediated activities that may promote human naive and 'extended' pluripotency'. We review the putative role of tankyrase and PARP inhibition in trophectoderm specification, telomere elongation, DNA repair and chromosomal segregation, metab., and PTEN-mediated apoptosis. Importantly, tankyrases possess PARP-independent activities that include regulation of MDC1-assocd. DNA repair by homologous recombination (HR) and autophagy/pexophagy, which is an essential mechanism of protein synthesis in the preimplantation embryo. Addnl., tankyrases auto-regulate themselves via auto-PARylation which augments their cellular protein levels and potentiates their non-PARP tankyrase functions. We propose that these non-PARP-related activities of tankyrase proteins may further independently affect both naive and extended pluripotency via mechanisms that remain undetd. We broadly outline a hypothetical framework for how inclusion of a tankyrase/PARP inhibitor in small mol. cocktails may stabilize and potentiate naive and extended pluripotency via pleiotropic routes and mechanisms.
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      Huang, S.-M. A.; Mishina, Y. M.; Liu, S.; Cheung, A.; Stegmeier, F.; Michaud, G. A.; Charlat, O.; Wiellette, E.; Zhang, Y.; Wiessner, S.; Hild, M.; Shi, X.; Wilson, C. J.; Mickanin, C.; Myer, V.; Fazal, A.; Tomlinson, R.; Serluca, F.; Shao, W.; Cheng, H.; Shultz, M.; Rau, C.; Schirle, M.; Schlegl, J.; Ghidelli, S.; Fawell, S.; Lu, C.; Curtis, D.; Kirschner, M. W.; Lengauer, C.; Finan, P. M.; Tallarico, J. A.; Bouwmeester, T.; Porter, J. A.; Bauer, A.; Cong, F. Tankyrase Inhibition Stabilizes Axin and Antagonizes Wnt Signalling. Nature 2009, 461, 614– 620,  DOI: 10.1038/nature08356
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      16
      Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
      Huang, Shih-Min A.; Mishina, Yuji M.; Liu, Shanming; Cheung, Atwood; Stegmeier, Frank; Michaud, Gregory A.; Charlat, Olga; Wiellette, Elizabeth; Zhang, Yue; Wiessner, Stephanie; Hild, Marc; Shi, Xiaoying; Wilson, Christopher J.; Mickanin, Craig; Myer, Vic; Fazal, Aleem; Tomlinson, Ronald; Serluca, Fabrizio; Shao, Wenlin; Cheng, Hong; Shultz, Michael; Rau, Christina; Schirle, Markus; Schlegl, Judith; Ghidelli, Sonja; Fawell, Stephen; Lu, Chris; Curtis, Daniel; Kirschner, Marc W.; Lengauer, Christoph; Finan, Peter M.; Tallarico, John A.; Bouwmeester, Tewis; Porter, Jeffery A.; Bauer, Andreas; Cong, Feng
      Nature (London, United Kingdom) (2009), 461 (7264), 614-620CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      The stability of the Wnt pathway transcription factor β-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited no. of pathway components that are amenable to small mol. inhibition. Here, we used a chem. genetic screen to identify a small mol., XAV939, which selectively inhibits β-catenin-mediated transcription. XAV939 stimulates β-catenin degrdn. by stabilizing axin, the concn.-limiting component of the destruction complex. Using a quant. chem. proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degrdn. through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.
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      Wang, Y.; Jiang, W.; Liu, X.; Zhang, Y. Tankyrase 2 (TNKS2) Polymorphism Associated with Risk in Developing Non-Small Cell Lung Cancer in a Chinese Population. Pathol., Res. Pract. 2015, 211, 766– 771,  DOI: 10.1016/j.prp.2015.07.003
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      Tankyrase 2 (TNKS2) polymorphism associated with risk in developing non-small cell lung cancer in a Chinese population
      Wang, Ying; Jiang, Weiyu; Liu, Xiaogu; Zhang, Yongjun
      Pathology, Research and Practice (2015), 211 (10), 766-771CODEN: PARPDS; ISSN:0344-0338. (Elsevier GmbH)
      We investigated the assocn. between poly(ADP-ribose) polymerase Tankyrase 2 (TNKS2) single-nucleotide polymorphisms (SNPs) and the risk of developing non-small cell lung cancer (NSCLC) in a Han Chinese population. Five-hundred NSCLC cases and 500 healthy controls were genotyped for four TNKS2 tagging SNPs (rs1538833, rs1538833, rs1340420, and rs1340420). The assocn. between genotype and NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) using multivariate unconditional logistic regression analyses. Individual alleles of the four TNKS2 SNPs were not assocd. with NSCLC risk in the studied Chinese population. However, patients carrying TNKS2 rs1340420 G/G and A/G genotypes were assocd. with a lower risk of developing NSCLC and adenocarcinoma (OR = 0.14; 95% CI = 0.02-1.15 and OR = 0.11; 95% CI = 0.03-0.91, resp.), whereas females patients homozygous for the TNKS2 rs1770474 T allele, a rare type, were assocd. with a higher risk of developing squamous-cell carcinoma (SCC) (OR = 4.67; 95% CI = 0.87-25.01). TNKS2 rs1340420 SNP was assocd. with lower NSCLC risk, whereas rs1770474 SNP was assocd. with higher SCC risk, suggesting that these two SNPs may be useful predictors of risk of developing NSCLC and SCC in this Chinese population.
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      Zamudio-Martinez, E.; Herrera-Campos, A. B.; Muñoz, A.; Rodríguez-Vargas, J. M.; Oliver, F. J. Tankyrases as Modulators of Pro-Tumoral Functions: Molecular Insights and Therapeutic Opportunities. J. Exp. Clin. Cancer Res. 2021, 40, 144  DOI: 10.1186/s13046-021-01950-6
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      Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities
      Zamudio-Martinez, Esteban; Herrera-Campos, Ana Belen; Munoz, Alberto; Rodriguez-Vargas, Jose Manuel; Oliver, F. Javier
      Journal of Experimental & Clinical Cancer Research (2021), 40 (1), 144CODEN: JECRDN; ISSN:1756-9966. (BioMed Central Ltd.)
      A review. Tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) are two homologous proteins that are gaining increasing importance due to their implication in multiple pathways and diseases such as cancer. TNKS1/2 interact with a large variety of substrates through the ankyrin (ANK) domain, which recognizes a sequence present in all the substrates of tankyrase, called Tankyrase Binding Motif (TBM). One of the main functions of tankyrases is the regulation of protein stability through the process of PARylation-dependent ubiquitination (PARdU). Nonetheless, there are other functions less studied that are also essential in order to understand the role of tankyrases in many pathways. In this , we conc. in different tankyrase substrates and we analyze in depth the biol. consequences derived of their interaction with TNKS1/2. We also examine the concept of both canonical and non-canonical TBMs and finally, we focus on the information about the role of TNKS1/2 in different tumor context, along with the benefits and limitations of the current TNKS inhibitors targeting the catalytic PARP domain and the novel strategies to develop inhibitors against the ankyrin domain. Available data indicates the need for further deepening in the knowledge of tankyrases to elucidate and improve the current view of the role of these PARP family members and get inhibitors with a better therapeutic and safety profile.
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      Liu, Z.; Wang, P.; Wold, E. A.; Song, Q.; Zhao, C.; Wang, C.; Zhou, J. Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer. J. Med. Chem. 2021, 64, 4257– 4288,  DOI: 10.1021/acs.jmedchem.0c01799
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      Small-Molecule Inhibitors Targeting the Canonical WNT Signaling Pathway for the Treatment of Cancer
      Liu, Zhiqing; Wang, Pingyuan; Wold, Eric A.; Song, Qiaoling; Zhao, Chenyang; Wang, Changyun; Zhou, Jia
      Journal of Medicinal Chemistry (2021), 64 (8), 4257-4288CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Canonical WNT signaling is an important developmental pathway that has attracted increased attention for anticancer drug discovery. From the prodn. and secretion of WNT ligands, their binding to membrane receptors, and the β-catenin destruction complex to the expansive β-catenin transcriptional complex, multiple components have been investigated as drug targets to modulate WNT signaling. Significant progress in developing WNT inhibitors such as porcupine inhibitors, tankyrase inhibitors, β-catenin/coactivators, protein-protein interaction inhibitors, casein kinase modulators, DVL inhibitors, and dCTPP1 inhibitors has been made, with several candidates (e.g., LGK-974, PRI-724, and ETC-159) in human clin. trials. Herein we summarize recent progress in the drug discovery and development of small-mol. inhibitors targeting the canonical WNT pathway, focusing on their specific target proteins, in vitro and in vivo activities, physicochem. properties, and therapeutic potential. The relevant opportunities and challenges toward maintaining the balance between efficacy and toxicity in effectively targeting this pathway are also highlighted.
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      Chen, B.; Dodge, M. E.; Tang, W.; Lu, J.; Ma, Z.; Fan, C.-W.; Wei, S.; Hao, W.; Kilgore, J.; Williams, N. S.; Roth, M. G.; Amatruda, J. F.; Chen, C.; Lum, L. Small Molecule–Mediated Disruption of Wnt-Dependent Signaling in Tissue Regeneration and Cancer. Nat. Chem. Biol. 2009, 5, 100– 107,  DOI: 10.1038/nchembio.137
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      Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer
      Chen, Baozhi; Dodge, Michael E.; Tang, Wei; Lu, Jianming; Ma, Zhiqiang; Fan, Chih-Wei; Wei, Shuguang; Hao, Wayne; Kilgore, Jessica; Williams, Noelle S.; Roth, Michael G.; Amatruda, James F.; Chen, Chuo; Lum, Lawrence
      Nature Chemical Biology (2009), 5 (2), 100-107CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
      The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small mols. that target Wnt-mediated cellular responses. By screening a diverse synthetic chem. library, we have discovered two new classes of small mols. that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the prodn. of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/β-catenin pathway activity. With these small mols., we establish a chem. genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/β-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chem. tractable addnl. contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chem. genetics and therapeutic goals.
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      Voronkov, A.; Holsworth, D. D.; Waaler, J.; Wilson, S. R.; Ekblad, B.; Perdreau-Dahl, H.; Dinh, H.; Drewes, G.; Hopf, C.; Morth, J. P.; Krauss, S. Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor. J. Med. Chem. 2013, 56, 3012– 3023,  DOI: 10.1021/jm4000566
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      Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor
      Voronkov, Andrew; Holsworth, Daniel D.; Waaler, Jo; Wilson, Steven R.; Ekblad, Bie; Perdreau-Dahl, Harmonie; Dinh, Huyen; Drewes, Gerard; Hopf, Carsten; Morth, Jens P.; Krauss, Stefan
      Journal of Medicinal Chemistry (2013), 56 (7), 3012-3023CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrases 1 and 2 (TNKS1/2) are promising pharmacol. biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chem. analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochem. IC50 values of 46 nM and 25 nM, resp., and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystd. with 66, and the X-ray structure was detd. at 2.8 Å resoln. in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compd.'s high target selectivity and specificity. Our study provides a significantly optimized compd. for targeting TNKS1/2 in vitro and in vivo.
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      Bregman, H.; Chakka, N.; Guzman-Perez, A.; Gunaydin, H.; Gu, Y.; Huang, X.; Berry, V.; Liu, J.; Teffera, Y.; Huang, L.; Egge, B.; Mullady, E. L.; Schneider, S.; Andrews, P. S.; Mishra, A.; Newcomb, J.; Serafino, R.; Strathdee, C. A.; Turci, S. M.; Wilson, C.; DiMauro, E. F. Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors. J. Med. Chem. 2013, 56, 4320– 4342,  DOI: 10.1021/jm4000038
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      Discovery of Novel, Induced-Pocket Binding Oxazolidinones as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
      Bregman, Howard; Chakka, Nagasree; Guzman-Perez, Angel; Gunaydin, Hakan; Gu, Yan; Huang, Xin; Berry, Virginia; Liu, Jingzhou; Teffera, Yohannes; Huang, Liyue; Egge, Bryan; Mullady, Erin L.; Schneider, Steve; Andrews, Paul S.; Mishra, Ankita; Newcomb, John; Serafino, Randy; Strathdee, Craig A.; Turci, Susan M.; Wilson, Cindy; DiMauro, Erin F.
      Journal of Medicinal Chemistry (2013), 56 (11), 4320-4342CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concns., resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compd. I is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and mol. modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (II, III).
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      Hua, Z.; Bregman, H.; Buchanan, J. L.; Chakka, N.; Guzman-Perez, A.; Gunaydin, H.; Huang, X.; Gu, Y.; Berry, V.; Liu, J.; Teffera, Y.; Huang, L.; Egge, B.; Emkey, R.; Mullady, E. L.; Schneider, S.; Andrews, P. S.; Acquaviva, L.; Dovey, J.; Mishra, A.; Newcomb, J.; Saffran, D.; Serafino, R.; Strathdee, C. A.; Turci, S. M.; Stanton, M.; Wilson, C.; DiMauro, E. F. Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors. J. Med. Chem. 2013, 56, 10003– 10015,  DOI: 10.1021/jm401317z
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      Development of Novel Dual Binders as Potent, Selective, and Orally Bioavailable Tankyrase Inhibitors
      Hua, Zihao; Bregman, Howard; Buchanan, John L.; Chakka, Nagasree; Guzman-Perez, Angel; Gunaydin, Hakan; Huang, Xin; Gu, Yan; Berry, Virginia; Liu, Jingzhou; Teffera, Yohannes; Huang, Liyue; Egge, Bryan; Emkey, Renee; Mullady, Erin L.; Schneider, Steve; Andrews, Paul S.; Acquaviva, Lisa; Dovey, Jennifer; Mishra, Ankita; Newcomb, John; Saffran, Douglas; Serafino, Randy; Strathdee, Craig A.; Turci, Susan M.; Stanton, Mary; Wilson, Cindy; DiMauro, Erin F.
      Journal of Medicinal Chemistry (2013), 56 (24), 10003-10015CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which neg. regulate the Wnt pathway by promoting β-catenin degrdn. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compd. N-(2-methoxyphenyl)-4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)propanamido)benzamide was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compd. collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein the authors report the structure- and property-based optimization of N-(2-methoxyphenyl)-4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)propanamido)benzamide leading to the identification of more potent and selective tankyrase inhibitors with improved pharmacokinetic properties in rodents, which are well suited as tool compds. for further in vivo validation studies.
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    24. 24
      McGonigle, S.; Chen, Z.; Wu, J.; Chang, P.; Kolber-Simonds, D.; Ackermann, K.; Twine, N. C.; Shie, J.; Miu, J. T.; Huang, K.-C.; Moniz, G. A.; Nomoto, K. E7449: A Dual Inhibitor of PARP1/2 and Tankyrase1/2 Inhibits Growth of DNA Repair Deficient Tumors and Antagonizes Wnt Signaling. Oncotarget 2015, 6, 41307– 41323,  DOI: 10.18632/oncotarget.5846
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      24
      E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling
      McGonigle Sharon; Chen Zhihong; Wu Jiayi; Kolber-Simonds Donna; Ackermann Karen; Twine Natalie C; Shie Jue-Lon; Miu Jingzang Tao; Huang Kuan-Chun; Nomoto Kenichi; Chang Paul; Chang Paul; Miu Jingzang Tao; Moniz George A; Moniz George A
      Oncotarget (2015), 6 (38), 41307-23 ISSN:.
      Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.
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    25. 25
      Paine, H. A.; Nathubhai, A.; Woon, E. C. Y.; Sunderland, P. T.; Wood, P. J.; Mahon, M. F.; Lloyd, M. D.; Thompson, A. S.; Haikarainen, T.; Narwal, M.; Lehtiö, L.; Threadgill, M. D. Exploration of the Nicotinamide-Binding Site of the Tankyrases, Identifying 3-Arylisoquinolin-1-Ones as Potent and Selective Inhibitors in Vitro. Bioorg. Med. Chem. 2015, 23, 5891– 5908,  DOI: 10.1016/j.bmc.2015.06.061
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      Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro
      Paine, Helen A.; Nathubhai, Amit; Woon, Esther C. Y.; Sunderland, Peter T.; Wood, Pauline J.; Mahon, Mary F.; Lloyd, Matthew D.; Thompson, Andrew S.; Haikarainen, Teemu; Narwal, Mohit; Lehtio, Lari; Threadgill, Michael D.
      Bioorganic & Medicinal Chemistry (2015), 23 (17), 5891-5908CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signaling). Using mol. modeling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesized by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, redn. and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Me and methoxy were optimal at the 5-position. SAR was rationalized by modeling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.
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    26. 26
      Nkizinkiko, Y.; Suneel Kumar, B. V. S.; Jeankumar, V. U.; Haikarainen, T.; Koivunen, J.; Madhuri, C.; Yogeeswari, P.; Venkannagari, H.; Obaji, E.; Pihlajaniemi, T.; Sriram, D.; Lehtiö, L. Discovery of Potent and Selective Nonplanar Tankyrase Inhibiting Nicotinamide Mimics. Bioorg. Med. Chem. 2015, 23, 4139– 4149,  DOI: 10.1016/j.bmc.2015.06.063
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      26
      Discovery of potent and selective nonplanar tankyrase inhibiting nicotinamide mimics
      Nkizinkiko, Yves; Suneel Kumar, B. V. S.; Jeankumar, Variam Ullas; Haikarainen, Teemu; Koivunen, Jarkko; Madhuri, Chanduri; Yogeeswari, Perumal; Venkannagari, Harikanth; Obaji, Ezeogo; Pihlajaniemi, Taina; Sriram, Dharmarajan; Lehtio, Lari
      Bioorganic & Medicinal Chemistry (2015), 23 (15), 4139-4149CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Diphtheria toxin-like ADP-ribosyltransferases catalyze a posttranslational modification, ADP-ribosylation and form a protein family of 17 members in humans. Two of the family members, tankyrases 1 and 2, are involved in several cellular processes including mitosis and Wnt/β-catenin signaling pathway. They are often over-expressed in cancer cells and have been linked with the survival of cancer cells making them potential therapeutic targets. In this study, the authors identified nine tankyrase inhibitors through virtual and in vitro screening. Crystal structures of tankyrase 2 with the compds. showed that they bind to the nicotinamide binding site of the catalytic domain. Based on the co-crystal structures the authors designed and synthesized a series of tetrahydroquinazolin-4-one and pyridopyrimidin-4-one analogs and were subsequently able to improve the potency of a hit compd. almost 100-fold (from 11 μM to 150 nM). The most potent compds. were selective towards tankyrases over a panel of other human ARTD enzymes. They also inhibited Wnt/β-catenin pathway in a cell-based reporter assay demonstrating the potential usefulness of the identified new scaffolds for further development.
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    27. 27
      Haikarainen, T.; Waaler, J.; Ignatev, A.; Nkizinkiko, Y.; Venkannagari, H.; Obaji, E.; Krauss, S.; Lehtiö, L. Development and Structural Analysis of Adenosine Site Binding Tankyrase Inhibitors. Bioorg. Med. Chem. Lett. 2016, 26, 328– 333,  DOI: 10.1016/j.bmcl.2015.12.018
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      27
      Development and structural analysis of adenosine site binding tankyrase inhibitors
      Haikarainen, Teemu; Waaler, Jo; Ignatev, Alexander; Nkizinkiko, Yves; Venkannagari, Harikanth; Obaji, Ezeogo; Krauss, Stefan; Lehtio, Lari
      Bioorganic & Medicinal Chemistry Letters (2016), 26 (2), 328-333CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
      Tankyrases 1 and 2, the specialized members of the ARTD protein family, are druggable biotargets whose inhibition may have therapeutic potential against cancer, metabolic disease, fibrotic disease, fibrotic wound healing and HSV viral infections. We have previously identified a novel tankyrase inhibitor scaffold, JW55, and showed that it reduces mouse colon adenoma formation in vivo. Here we expanded the scaffold and profiled the selectivity of the compds. against a panel of human ARTDs. The scaffold also enables a fine modulation of selectivity towards either tankyrase 1 or tankyrase 2. In order to get insight about the binding mode of the inhibitors, we solved crystal structures of the compds. in complex with tankyrase 2. The compds. bind to the adenosine pocket of the catalytic domain and cause changes in the protein structure that are modulated by the chem. modifications of the compds. The structural anal. allows further rational development of this compd. class as a potent and selective tankyrase inhibitor.
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    28. 28
      Anumala, U. R.; Waaler, J.; Nkizinkiko, Y.; Ignatev, A.; Lazarow, K.; Lindemann, P.; Olsen, P. A.; Murthy, S.; Obaji, E.; Majouga, A. G.; Leonov, S.; von Kries, J. P.; Lehtiö, L.; Krauss, S.; Nazaré, M. Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach. J. Med. Chem. 2017, 60, 10013– 10025,  DOI: 10.1021/acs.jmedchem.7b00883
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      28
      Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
      Anumala, Upendra Rao; Waaler, Jo; Nkizinkiko, Yves; Ignatev, Alexander; Lazarow, Katina; Lindemann, Peter; Olsen, Petter Angell; Murthy, Sudarshan; Obaji, Ezeogo; Majouga, Alexander G.; Leonov, Sergey; von Kries, Jens Peter; Lehtioe, Lari; Krauss, Stefan; Nazare, Marc
      Journal of Medicinal Chemistry (2017), 60 (24), 10013-10025CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A structure-guided hybridization approach using two privileged substructures gave instant access to a new series of tankyrase inhibitors. The identified inhibitor 16 (1-(trans-3-(4-(2-Chlorophenyl)-5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)cyclobutyl)-2,3-dihydro-2-oxo-1H-benzimidazole-5-carbonitrile) displays high target affinity on tankyrase 1 and 2 with biochem. and cellular IC50 values of 29 nM, 6.3 nM and 19 nM, resp., and high selectivity toward other poly (ADP-ribose) polymerase enzymes. The identified inhibitor shows a favorable in vitro ADME profile as well as good oral bioavailability in mice, rats, and dogs. Crit. for the approach was the utilization of an appropriate linker between 1,2,4-triazole and benzimidazolone moieties, whereby a cyclobutyl linker displayed superior affinity compared to a cyclohexane and Ph linker.
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    29. 29
      Ferri, M.; Liscio, P.; Carotti, A.; Asciutti, S.; Sardella, R.; Macchiarulo, A.; Camaioni, E. Targeting Wnt-Driven Cancers: Discovery of Novel Tankyrase Inhibitors. Eur. J. Med. Chem. 2017, 142, 506– 522,  DOI: 10.1016/j.ejmech.2017.09.030
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      29
      Targeting Wnt-driven cancers: Discovery of novel tankyrase inhibitors
      Ferri, Martina; Liscio, Paride; Carotti, Andrea; Asciutti, Stefania; Sardella, Roccaldo; Macchiarulo, Antonio; Camaioni, Emidio
      European Journal of Medicinal Chemistry (2017), 142 (), 506-522CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A review. Recent years have seen substantially heightened interest in the discovery of tankyrase inhibitors (TNKSi) as new promising anticancer agents. In this framework, the aim of this review article is focused on the description of potent TNKSi also endowed with disruptor activity toward the Wnt/β-catenin signaling pathway. Beginning with an overview of the most characterized TNKSi deriving from several drug design approaches and classifying them on the basis of the mol. interactions with the target, the authors discuss only those ones acting against Wnt cancer cell lines. In addn., comprehensive structure property relationships (SPR) emerging from the hit evolution processes and preclin. results are provided. The authors then review the most promising TNKSi hitherto reported in literature, acting in vivo models of Wnt-driven cancers. Some out-looks on current issues and future directions in this field are also discussed.
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    30. 30
      Di Micco, S.; Pulvirenti, L.; Bruno, I.; Terracciano, S.; Russo, A.; Vaccaro, M. C.; Ruggiero, D.; Muccilli, V.; Cardullo, N.; Tringali, C.; Riccio, R.; Bifulco, G. Identification by Inverse Virtual Screening of Magnolol-Based Scaffold as New Tankyrase-2 Inhibitors. Bioorg. Med. Chem. 2018, 26, 3953– 3957,  DOI: 10.1016/j.bmc.2018.06.019
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      30
      Identification by Inverse Virtual Screening of magnolol-based scaffold as new tankyrase-2 inhibitors
      Di Micco, Simone; Pulvirenti, Luana; Bruno, Ines; Terracciano, Stefania; Russo, Alessandra; Vaccaro, Maria C.; Ruggiero, Dafne; Muccilli, Vera; Cardullo, Nunzio; Tringali, Corrado; Riccio, Raffaele; Bifulco, Giuseppe
      Bioorganic & Medicinal Chemistry (2018), 26 (14), 3953-3957CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      The natural product magnolol (1) and a selection of its bioinspired derivs. 2-5, were investigated by Inverse Virtual Screening in order to identify putative biol. targets from a panel of 308 proteins involved in cancer processes. By this in silico anal. we selected tankyrase-2 (TNKS2), casein kinase 2 (CK2) and bromodomain 9 (Brd9) as potential targets for exptl. evaluations. The Surface Plasmon Resonance assay revealed that 3-5 present a good affinity for tankyrase-2, and, in particular, 3 showed an antiproliferative activity on A549 cells higher than the well-known tankyrase-2 inhibitor XAV939 used as ref. compd.
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    31. 31
      Mizutani, A.; Yashiroda, Y.; Muramatsu, Y.; Yoshida, H.; Chikada, T.; Tsumura, T.; Okue, M.; Shirai, F.; Fukami, T.; Yoshida, M.; Seimiya, H. RK-287107, a Potent and Specific Tankyrase Inhibitor, Blocks Colorectal Cancer Cell Growth in a Preclinical Model. Cancer Sci. 2018, 109, 4003– 4014,  DOI: 10.1111/cas.13805
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      RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model
      Mizutani, Anna; Yashiroda, Yoko; Muramatsu, Yukiko; Yoshida, Haruka; Chikada, Tsubasa; Tsumura, Takeshi; Okue, Masayuki; Shirai, Fumiyuki; Fukami, Takehiro; Yoshida, Minoru; Seimiya, Hiroyuki
      Cancer Science (2018), 109 (12), 4003-4014CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)
      Tankyrase poly(ADP-ribosyl)ates (PARylates) Axin, a neg. regulator of β-catenin. This post-translational modification causes ubiquitin-dependent degrdn. of Axin, resulting in β-catenin accumulation. Tankyrase inhibitors downregulate β-catenin and suppress the growth of APC-mutated colorectal cancer cells. Herein, we report a novel tankyrase-specific inhibitor RK-287107, which inhibits tankyrase-1 and -2 four- and eight-fold more potently, resp., than G007-LK, a tankyrase inhibitor that has been previously reported as effective in mouse xenograft models. RK-287107 causes Axin2 accumulation and downregulates β-catenin, T-cell factor/lymphoid enhancer factor reporter activity and the target gene expression in colorectal cancer cells harboring the shortly truncated APC mutations. Consistently, RK-287107 inhibits the growth of APC-mutated (β-catenin-dependent) colorectal cancer COLO-320DM and SW403 cells but not the APC-wild (β-catenin-independent) colorectal cancer RKO cells. I.p. or oral administration of RK-287107 suppresses COLO-320DM tumor growth in NOD-SCID mice. Rates of tumor growth inhibition showed good correlation with the behavior of pharmacodynamic biomarkers, such as Axin2 accumulation and MYC downregulation. These observations indicate that RK-287107 exerts a proof-of-concept antitumor effect, and thus may have potential for tankyrase-directed mol. cancer therapy.
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    32. 32
      Menon, M.; Elliott, R.; Bowers, L.; Balan, N.; Rafiq, R.; Costa-Cabral, S.; Munkonge, F.; Trinidade, I.; Porter, R.; Campbell, A. D.; Johnson, E. R.; Esdar, C.; Buchstaller, H.-P.; Leuthner, B.; Rohdich, F.; Schneider, R.; Sansom, O.; Wienke, D.; Ashworth, A.; Lord, C. J. A Novel Tankyrase Inhibitor, MSC2504877, Enhances the Effects of Clinical CDK4/6 Inhibitors. Sci. Rep. 2019, 9, 201216  DOI: 10.1038/s41598-018-36447-4
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      There is no corresponding record for this reference.
    33. 33
      Shirai, F.; Tsumura, T.; Yashiroda, Y.; Yuki, H.; Niwa, H.; Sato, S.; Chikada, T.; Koda, Y.; Washizuka, K.; Yoshimoto, N.; Abe, M.; Onuki, T.; Mazaki, Y.; Hirama, C.; Fukami, T.; Watanabe, H.; Honma, T.; Umehara, T.; Shirouzu, M.; Okue, M.; Kano, Y.; Watanabe, T.; Kitamura, K.; Shitara, E.; Muramatsu, Y.; Yoshida, H.; Mizutani, A.; Seimiya, H.; Yoshida, M.; Koyama, H. Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors. J. Med. Chem. 2019, 62, 3407– 3427,  DOI: 10.1021/acs.jmedchem.8b01888
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      Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors
      Shirai, Fumiyuki; Tsumura, Takeshi; Yashiroda, Yoko; Yuki, Hitomi; Niwa, Hideaki; Sato, Shin; Chikada, Tsubasa; Koda, Yasuko; Washizuka, Kenichi; Yoshimoto, Nobuko; Abe, Masako; Onuki, Tetsuo; Mazaki, Yui; Hirama, Chizuko; Fukami, Takehiro; Watanabe, Hirofumi; Honma, Teruki; Umehara, Takashi; Shirouzu, Mikako; Okue, Masayuki; Kano, Yuko; Watanabe, Takashi; Kitamura, Kouichi; Shitara, Eiki; Muramatsu, Yukiko; Yoshida, Haruka; Mizutani, Anna; Seimiya, Hiroyuki; Yoshida, Minoru; Koyama, Hiroo
      Journal of Medicinal Chemistry (2019), 62 (7), 3407-3427CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin signal by preventing poly ADP-ribosylation dependent degrdn. of AXIN, a neg. regulator of Wnt/β-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small mol. inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a(I), a high-throughput screening hit, the spiroindoline deriv. 40c(II) (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7,000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. II also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that II is a promising lead compd. for the development of novel tankyrase inhibitors as anticancer agents.
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    34. 34
      Buchstaller, H.-P.; Anlauf, U.; Dorsch, D.; Kuhn, D.; Lehmann, M.; Leuthner, B.; Musil, D.; Radtki, D.; Ritzert, C.; Rohdich, F.; Schneider, R.; Esdar, C. Discovery and Optimization of 2-Arylquinazolin-4-Ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity. J. Med. Chem. 2019, 62, 7897– 7909,  DOI: 10.1021/acs.jmedchem.9b00656
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      Discovery and Optimization of 2-Arylquinazolin-4-ones into a Potent and Selective Tankyrase Inhibitor Modulating Wnt Pathway Activity
      Buchstaller, Hans-Peter; Anlauf, Uwe; Dorsch, Dieter; Kuhn, Daniel; Lehmann, Martin; Leuthner, Birgitta; Musil, Djordje; Radtki, Daniela; Ritzert, Claudio; Rohdich, Felix; Schneider, Richard; Esdar, Christina
      Journal of Medicinal Chemistry (2019), 62 (17), 7897-7909CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrases 1 and 2 (TNKS1/2) are promising pharmacol. targets which recently gained interest for anticancer therapy in Wnt pathway dependent tumors. 2-Aryl-quinazolinones were identified and optimized into potent tankyrase inhibitors through SAR exploration around the quinazolinone core and the 4'-position of the Ph residue. These efforts were supported by anal. of TNKS X-ray and Watermap structures and resulted in compd. 5k(I), a potent, selective tankyrase inhibitor with favorable pharmacokinetic properties. The X-ray structure of I in complex with TNKS1 was solved and confirmed the design hypothesis. Modulation of Wnt pathway activity was demonstrated with this compd. in a colorectal xenograft model in vivo.
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    35. 35
      Sabnis, R. W. Novel 4-Heteroarylcarbonyl-N-(Phenyl or Heteroaryl) Piperidine-1-Carboxamides as Tankyrase Inhibitors. ACS Med. Chem. Lett. 2020, 11, 1676– 1677,  DOI: 10.1021/acsmedchemlett.0c00390
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      Novel 4-Heteroarylcarbonyl-N-(phenyl or heteroaryl) Piperidine-1-carboxamides as Tankyrase Inhibitors
      Sabnis, Ram W.
      ACS Medicinal Chemistry Letters (2020), 11 (9), 1676-1677CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      There is no expanded citation for this reference.
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    36. 36
      Kinosada, H.; Okada-Iwasaki, R.; Kunieda, K.; Suzuki-Imaizumi, M.; Takahashi, Y.; Miyagi, H.; Suzuki, M.; Motosawa, K.; Watanabe, M.; Mie, M.; Ishii, T.; Ishida, H.; Saito, J.-I.; Nakai, R. The Dual Pocket Binding Novel Tankyrase Inhibitor K-476 Enhances the Efficacy of Immune Checkpoint Inhibitor by Attracting CD8+ T Cells to Tumors. Am. J. Cancer Res. 2021, 11, 264– 276
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      The dual pocket binding novel tankyrase inhibitor K-476 enhances the efficacy of immune checkpoint inhibitor by attracting CD8+ T cells to tumors
      Kinosada, Haruka; Okada-Iwasaki, Ryoko; Kunieda, Kana; Suzuki-Imaizumi, Minami; Takahashi, Yuichi; Miyagi, Hikaru; Suzuki, Michihiko; Motosawa, Keiichi; Watanabe, Miwa; Mie, Motoya; Ishii, Toshihiko; Ishida, Hiroshi; Saito, Jun-ichi; Nakai, Ryuichiro
      American Journal of Cancer Research (2021), 11 (1), 264-276CODEN: AJCRFT; ISSN:2156-6976. (e-Century Publishing Corp.)
      The Wnt/β-catenin pathway, which is assocd. with disease progression, is activated in many cancers. Tankyrase (TNKS) has received attention as a target mol. for Wnt/β-catenin pathway inhibition. We identified K-476, a novel TNKS inhibitor, a dual pocket binder that binds to both the nicotinamide and ADP-ribose pockets. In a human colon cancer cell line, K-476 specifically and potently inhibited TNKS and led to stabilization of the Axin protein, resulting in Wnt/β-catenin pathway suppression. Aberrant Wnt/β-catenin pathway activation was recently reported as a possible mechanism of ineffectiveness in immune checkpoint inhibitor (ICI) treatment. Because the Wnt/β-catenin pathway activation causes dendritic cell inactivation and suppresses chemokine prodn., resulting in a paucity of CD8+ T cells in tumor tissue, which is an important effector of ICIs. Thus, TNKS inhibitors may enhance the efficacy of ICIs. To examine whether K-476 enhances the antitumor effect of anti-PD-L1 antibodies, K-476 was administered orally with an anti-PD-L1 antibody to melanoma-bearing C57BL/6J mice. Although K-476 was ineffective as a monotherapy, it significantly enhanced the antitumor effect in combination with anti-PD-L1 antibody. In mice, intra-tumor infiltration of CD8+ T cells was increased by combination treatment. K-476 upregulated the chemokine expression (e.g., Ccl3 and Ccl4), which attracted CD8+ T cells. This was considered to contribute to the increased CD8+ T cells in the tumor microenvironment. Furthermore, while the potential gastrointestinal toxicity of TNKS inhibitors has been reported, it was not obsd. at EDs. Thus, K-476 could be an attractive therapeutic option to enhance the efficacy of ICIs.
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    37. 37
      Mehta, C. C.; Bhatt, H. G. Tankyrase Inhibitors as Antitumor Agents: A Patent Update (2013 – 2020). Expert Opin. Ther. Pat. 2021, 31, 645– 661,  DOI: 10.1080/13543776.2021.1888929
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      Tankyrase inhibitors as antitumor agents: a patent update (2013 - 2020)
      Mehta, Chirag C.; Bhatt, Hardik G.
      Expert Opinion on Therapeutic Patents (2021), 31 (7), 645-661CODEN: EOTPEG; ISSN:1354-3776. (Taylor & Francis Ltd.)
      IntroductionTankyrase inhibitors gained significant attention as therapeutic targets in oncol. because of their potency. Their primary role in inhibiting the Wnt signaling pathway makes them an important class of compds. with the potential to be used as a combination therapy in future treatments of colorectal cancer. Areas coveredThis review describes pertinent work in the development of tankyrase inhibitors with a great emphasis on the recently patented TNKS inhibitors published from 2013 to 2020. This article also highlights a couple of promising candidates having tankyrase inhibitory effects and are currently undergoing clin. trials. Expert opinionFollowing the successful clin. applications of PARP inhibitors, tankyrase inhibition has gained significant attention in the research community as a target with high therapeutic potential. The ubiquitous role of tankyrase in cellular homeostasis and Wnt-dependent tumor proliferation brought difficulties for researchers to strike the right balance between potency and on-target toxicity. The need for novel tankyrase inhibitors with a better ADMET profile can introduce an addnl. regimen in treating various malignancies in monotherapy or adjuvant therapy. The development of combination therapies, including tankyrase inhibitors with or without PARP inhibitory properties, can potentially benefit the larger population of patients with unmet medical needs.
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    38. 38
      Waaler, J.; Machon, O.; Kries, J. P.; von Wilson, S. R.; Lundenes, E.; Wedlich, D.; Gradl, D.; Paulsen, J. E.; Machonova, O.; Dembinski, J. L.; Dinh, H.; Krauss, S. Novel Synthetic Antagonists of Canonical Wnt Signaling Inhibit Colorectal Cancer Cell Growth. Cancer Res. 2011, 71, 197– 205,  DOI: 10.1158/0008-5472.CAN-10-1282
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      Novel Synthetic Antagonists of Canonical Wnt Signaling Inhibit Colorectal Cancer Cell Growth
      Waaler, Jo; Machon, Ondrej; von Kries, Jens Peter; Wilson, Steven Ray; Lundenes, Elsa; Wedlich, Doris; Gradl, Dietmar; Paulsen, Jan Erik; Machonova, Olga; Dembinski, Jennifer L.; Dinh, Huyen; Krauss, Stefan
      Cancer Research (2011), 71 (1), 197-205CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      Canonical Wnt signaling is deregulated in several types of human cancer where it plays a central role in tumor cell growth and progression. Here we report the identification of 2 new small mols. that specifically inhibit canonical Wnt pathway at the level of the destruction complex. Specificity was verified in various cellular reporter systems, a Xenopus double-axis formation assay and a gene expression profile anal. In human colorectal cancer (CRC) cells, the new compds. JW67 and JW74 rapidly reduced active β-catenin with a subsequent downregulation of Wnt target genes, including AXIN2, SP5, and NKD1. Notably, AXIN2 protein levels were strongly increased after compd. exposure. Long-term treatment with JW74 inhibited the growth of tumor cells in both a mouse xenograft model of CRC and in ApcMin mice (multiple intestinal neoplasia, Min). Our findings rationalize further preclin. and clin. evaluation of these new compds. as novel modalities for cancer treatment. Cancer Res; 71(1); 197-205.
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    39. 39
      Waaler, J.; Leenders, R. G. G.; Sowa, S. T.; Alam Brinch, S.; Lycke, M.; Nieczypor, P.; Aertssen, S.; Murthy, S.; Galera-Prat, A.; Damen, E.; Wegert, A.; Nazaré, M.; Lehtiö, L.; Krauss, S. Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor. J. Med. Chem. 2020, 63, 6834– 6846,  DOI: 10.1021/acs.jmedchem.0c00208
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      39
      Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor
      Waaler, Jo; Leenders, Ruben G. G.; Sowa, Sven T.; Alam Brinch, Shoshy; Lycke, Max; Nieczypor, Piotr; Aertssen, Sjoerd; Murthy, Sudarshan; Galera-Prat, Albert; Damen, Eddy; Wegert, Anita; Nazare, Marc; Lehtio, Lari; Krauss, Stefan
      Journal of Medicinal Chemistry (2020), 63 (13), 6834-6846CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compd. 1 (I) were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compds. reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 (II) resolves previous atropisomerism, soly., and Caco-2 efflux liabilities. 13 Shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.
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      Zhong, Y.; Katavolos, P.; Nguyen, T.; Lau, T.; Boggs, J.; Sambrone, A.; Kan, D.; Merchant, M.; Harstad, E.; Diaz, D.; Costa, M.; Schutten, M. Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index <1. Toxicol. Pathol. 2016, 44, 267– 278,  DOI: 10.1177/0192623315621192
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      Tankyrase inhibition causes reversible intestinal toxicity in mice with a therapeutic index < 1
      Zhong, Yu; Katavolos, Paula; Nguyen, Trung; Lau, Ted; Boggs, Jason; Sambrone, Amy; Kan, David; Merchant, Mark; Harstad, Eric; Diaz, Dolores; Costa, Mike; Schutten, Melissa
      Toxicologic Pathology (2016), 44 (2), 267-278CODEN: TOPADD; ISSN:0192-6233. (Sage Publications)
      Activated Wnt/β-catenin signaling is frequently assocd. with colorectal cancer. Wnt inhibitors, including tankyrase inhibitors, are being explored as potential anticancer agents. Wnt signaling is also crit. for intestinal tissue homeostasis, and Wnt inhibitors have been shown to cause intestinal toxicity in mice by affecting intestinal stem cells. This study sought to characterize the intestinal toxicity of tankyrase inhibitors, including reversibility, and to assess their therapeutic index. Novel tankyrase inhibitor G-631 caused dose-dependent intestinal toxicity with a therapeutic index < 1 after 14 days of dosing in mice. At a tolerated subtherapeutic dose level, the intestinal toxicity was composed of enteritis characterized by villus blunting, epithelial degeneration, and inflammation, which fully reversed after 14 days of recovery. Doubled exposure showed weak antitumor activity in a xenograft colorectal cancer model but also caused more severe intestinal toxicity characterized by multifocal-regionally extensive necrotizing and ulcerative enteritis leading to morbidity or moribundity in some animals. This toxicity was only partially reversed after 14 days of recovery, with evidence of crypt and villus regeneration, mildly blunted villi, and/or scarring in assocn. with chronic inflammation of the submucosa. Therefore, the clin. utility of tankyrase inhibitors is likely limited by the on-target intestinal toxicity and a therapeutic index < 1 in mice.
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      Qin, D.; Lin, X.; Liu, Z.; Chen, Y.; Zhang, Z.; Wu, C.; Liu, L.; Pan, Y.; Laquerre, S.; Emery, J.; Fergusson, J.; Roland, K.; Keenan, R.; Oliff, A.; Kumar, S.; Cheung, M.; Su, D.-S. Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors. ACS Med. Chem. Lett. 2021, 12, 1005– 1010,  DOI: 10.1021/acsmedchemlett.1c00160
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      Discovery of Orally Bioavailable Ligand Efficient Quinazolinediones as Potent and Selective Tankyrases Inhibitors
      Qin, Donghui; Lin, Xiaojuan; Liu, Zhi; Chen, Yan; Zhang, Zhiliu; Wu, Chengde; Liu, Linlin; Pan, Yan; Laquerre, Sylvie; Emery, John; Fergusson, Jeff; Roland, Kimberly; Keenan, Rick; Oliff, Allen; Kumar, Sanjay; Cheung, Mui; Su, Dai-Shi
      ACS Medicinal Chemistry Letters (2021), 12 (6), 1005-1010CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      The authors report the discovery of quinazolinediones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compd. I (R1 = R2 = R3 = H, R4 = NHCH2Ph), led to truncated analogs, e.g., I (R1 = H, F, Cl, OMe, Me, R2 = H, F, Me, CONH2, R3 = H, CF3, Me, Cl, R4 = OH, 4-pyridylamino, 1-methyl-4-pyrazolylamino, etc.), that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compd. I (R1 = R2 = H, R3 = CF3, R4 = OH) (II) exhibited excellent potencies in cells and proliferation studies, good selectivity, in vitro activities, and an excellent PK profile. Compd. II also inhibited H292 xenograft tumor growth in nude mice. The synthesis, biol., pharmacokinetic, in vivo efficacy studies, and safety profiles of compds. are presented.
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      Kwak, Y. H.; Barrientos, T.; Furman, B.; Zhang, H.; Puviindran, V.; Cutcliffe, H.; Herfarth, J.; Nwankwo, E.; Alman, B. A. Pharmacologic Targeting of β-Catenin Improves Fracture Healing in Old Mice. Sci. Rep. 2019, 9, 9005  DOI: 10.1038/s41598-019-45339-0
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      Pharmacologic targeting of β-catenin improves fracture healing in old mice
      Kwak Yoon Hae; Barrientos Tomasa; Furman Bridgette; Zhang Hazel; Puviindran Vijitha; Cutcliffe Hattie; Herfarth Jonas; Nwankwo Eugene; Alman Benjamin A; Kwak Yoon Hae; Alman Benjamin A
      Scientific reports (2019), 9 (1), 9005 ISSN:.
      β-catenin protein needs to be precisely regulated for effective fracture repair. The pace of fracture healing slows with age, associated with a transient increase in β-catenin during the initial phase of the repair process. Here we examined the ability of pharmacologic agents that target β-catenin to improve the quality of fracture repair in old mice. 20 month old mice were treated with Nefopam or the tankyrase inhibitor XAV939 after a tibia fracture. Fractures were examined 21 days later by micro-CT and histology, and 28 days later using mechanical testing. Daily treatment with Nefopam for three or seven days but not ten days improved the amount of bone present at the fracture site, inhibited β-catenin protein level, and increased colony forming units osteoblastic from bone marrow cells. At 28 days, treatment increased the work to fracture of the injured tibia. XAV939 had a more modest effect on β-catenin protein, colony forming units osteoblastic, and the amount of bone at the fracture site. This data supports the notion that high levels of β-catenin in the early phase of fracture healing in old animals slows osteogenesis, and suggests a pharmacologic approach that targets β-catenin to improve fracture repair in the elderly.
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      Zhong, L.; Ding, Y.; Bandyopadhyay, G.; Waaler, J.; Börgeson, E.; Smith, S.; Zhang, M.; Phillips, S. A.; Mahooti, S.; Mahata, S. K.; Shao, J.; Krauss, S.; Chi, N.-W. The PARsylation Activity of Tankyrase in Adipose Tissue Modulates Systemic Glucose Metabolism in Mice. Diabetologia 2016, 59, 582– 591,  DOI: 10.1007/s00125-015-3815-1
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      The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice
      Zhong, Linlin; Ding, Yun; Bandyopadhyay, Gautam; Waaler, Jo; Borgeson, Emma; Smith, Susan; Zhang, Mingchen; Phillips, Susan A.; Mahooti, Sepi; Mahata, Sushil K.; Shao, Jianhua; Krauss, Stefan; Chi, Nai-Wen
      Diabetologia (2016), 59 (3), 582-591CODEN: DBTGAJ; ISSN:0012-186X. (Springer)
      Aims/hypothesis: Tankyrase (TNKS) is a ubiquitously expressed mol. scaffold that is implicated in diverse processes. The catalytic activity of TNKS modifies substrate proteins through poly-ADP-ribosylation (PARsylation) and is responsive to cellular energetic state. Global deficiency of the TNKS protein in mice accelerates glucose utilization and raises plasma adiponectin levels. The aim of this study was to investigate whether the PARsylation activity of TNKS in adipocytes plays a role in systemic glucose homeostasis. Methods: To inhibit TNKS-mediated PARsylation, we fed mice with a diet contg. the TNKS-specific inhibitor G007-LK. To genetically inactivate TNKS catalysis in adipocytes while preserving its function as a mol. scaffold, we used an adipocyte-selective Cre transgene to delete TNKS exons that encoded the catalytic domain at the C-terminus. Tissue-specific insulin sensitivity in mice was investigated using hyperinsulinemic-euglycemic clamps. To model adipose-liver crosstalk ex vivo, we applied adipocyte-conditioned media to hepatocytes and assessed the effect on gluconeogenesis. Results: The TNKS inhibitor G007-LK improved glucose tolerance and insulin sensitivity and promptly increased plasma adiponectin levels. In female mice, but not in male mice, adipocyte-selective genetic inactivation of TNKS catalysis improved hepatic insulin sensitivity and post-transcriptionally increased plasma adiponectin levels. Both pharmacol. and genetic TNKS inhibition in female mouse-derived adipocytes induced a change in secreted factors to decrease gluconeogenesis in primary hepatocytes. Conclusions/interpretation: Systemic glucose homeostasis is regulated by the PARsylation activity of TNKS in adipocytes. This regulation is mediated in part by adipocyte-secreted factors that modulate hepatic glucose prodn. Pharmacol. TNKS inhibition could potentially be used to improve glucose tolerance.
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    44. 44
      Plummer, R.; Dua, D.; Cresti, N.; Drew, Y.; Stephens, P.; Foegh, M.; Knudsen, S.; Sachdev, P.; Mistry, B. M.; Dixit, V.; McGonigle, S.; Hall, N.; Matijevic, M.; McGrath, S.; Sarker, D. First-in-Human Study of the PARP/Tankyrase Inhibitor E7449 in Patients with Advanced Solid Tumours and Evaluation of a Novel Drug-Response Predictor. Br. J. Cancer 2020, 123, 525– 533,  DOI: 10.1038/s41416-020-0916-5
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      First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor
      Plummer, Ruth; Dua, Divyanshu; Cresti, Nicola; Drew, Yvette; Stephens, Peter; Foegh, Marie; Knudsen, Steen; Sachdev, Pallavi; Mistry, Bipin M.; Dixit, Vaishali; McGonigle, Sharon; Hall, Nancy; Matijevic, Mark; McGrath, Shannon; Sarker, Debashis
      British Journal of Cancer (2020), 123 (4), 525-533CODEN: BJCAAI; ISSN:0007-0920. (Nature Research)
      This phase 1 study examd. the safety, max.-tolerated dose (MTD) and antitumor activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumors (50-800-mg doses). Archival tumor samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumor types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumor activity in solid tumors, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 wk) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumor activity and significant concn.-dependent PARP inhibition following 50-800-mg oral dosing. The results support further clin. investigation of E7449 and its assocd. biomarker 2X-121 DRP.
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      Clinical-Trials-Registry/NCT01618136 and NCT04505839.
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      Pereira, J. A.; Pessoa, A. M.; Cordeiro, M. N. D. S.; Fernandes, R.; Prudêncio, C.; Noronha, J. P.; Vieira, M. Quinoxaline, Its Derivatives and Applications: A State of the Art Review. Eur. J. Med. Chem. 2015, 97, 664– 672,  DOI: 10.1016/j.ejmech.2014.06.058
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      Quinoxaline, its derivatives and applications: A State of the Art review
      Pereira, Joana A.; Pessoa, Ana M.; Cordeiro, M. Natalia D. S.; Fernandes, Ruben; Prudencio, Cristina; Noronha, Joao Paulo; Vieira, Monica
      European Journal of Medicinal Chemistry (2015), 97 (), 664-672CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)
      A review. Quinoxaline derivs. are an important class of heterocycle compds., where N replaces some carbon atoms in the ring of naphthalene. Its mol. formula is C8H6N2, formed by the fusion of two arom. rings, benzene and pyrazine. It is rare in natural state, but their synthesis is easy to perform. In this review the State of the Art will be presented, which includes a summary of the progress made over the past years in the knowledge of the structure and mechanism of the quinoxaline and quinoxaline derivs., assocd. medical and biomedical value as well as industrial value. Modifying quinoxaline structure it is possible to obtain a wide variety of biomedical applications, namely antimicrobial activities and chronic and metabolic diseases treatment.
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      Baumeister, S.; Schepmann, D.; Wünsch, B. Synthesis and Receptor Binding of Thiophene Bioisosteres of Potent GluN2B Ligands with a Benzo[7]Annulene-Scaffold. Med. Chem. Commun. 2019, 10, 315– 325,  DOI: 10.1039/C8MD00545A
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      Quinn, L. A.; Moore, G. E.; Morgan, R. T.; Woods, L. K. Cell Lines from Human Colon Carcinoma with Unusual Cell Products, Double Minutes, and Homogeneously Staining Regions. Cancer Res. 1979, 39, 4914– 4924
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      Cell lines from human colon carcinoma with unusual cell products, double minutes, and homogeneously staining regions
      Quinn L A; Moore G E; Morgan R T; Woods L K
      Cancer research (1979), 39 (12), 4914-24 ISSN:0008-5472.
      Two human colon carcinoma cell lines derived from the same tumor specimen were characterized. The cell lines, COLO 320 and COLO 321, have amine precursor uptake and decarboxylation cell properties, such as ectopic production of norepinephrine, epinephrine, serotonin, adrenocorticotropic hormone, and parathyroid hormone. The cells were morphologically different from most colon cell lines. Double minutes (DM) were initially present in nearly 100% of the metaphases. In a few subcultures of COLO 320, DM have persisted for 1.5 years. However, in COLO 321 and some subcultures of COLO 320, a loss of DM was observed and new marker chromosomes with homogeneously staining regions were observed. These unusual cell lines should be valuable for studies of apudomas of the colon and the cytogenetic phenomena of DM and homogeneously staining regions.
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    49. 49
      Lau, T.; Chan, E.; Callow, M.; Waaler, J.; Boggs, J.; Blake, R. A.; Magnuson, S.; Sambrone, A.; Schutten, M.; Firestein, R.; Machon, O.; Korinek, V.; Choo, E.; Diaz, D.; Merchant, M.; Polakis, P.; Holsworth, D. D.; Krauss, S.; Costa, M. A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation–Driven Colorectal Tumor Growth. Cancer Res. 2013, 73, 3132– 3144,  DOI: 10.1158/0008-5472.CAN-12-4562
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      A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation-Driven Colorectal Tumor Growth
      Lau, Ted; Chan, Emily; Callow, Marinella; Waaler, Jo; Boggs, Jason; Blake, Robert A.; Magnuson, Steven; Sambrone, Amy; Schutten, Melissa; Firestein, Ron; Machon, Ondrej; Korinek, Vladimir; Choo, Edna; Diaz, Dolores; Merchant, Mark; Polakis, Paul; Holsworth, Daniel D.; Krauss, Stefan; Costa, Mike
      Cancer Research (2013), 73 (10), 3132-3144CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin-mediated signaling. However, continued requirement of Wnt/P-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-mol. tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt./p-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degrdn., thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approx. 50% inhibition of APC mutation-driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compd. G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin-dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity assocd. with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic.
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    50. 50
      Solberg, N. T.; Waaler, J.; Lund, K.; Mygland, L.; Olsen, P. A.; Krauss, S. TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer. Mol Cancer Res. 2018, 16, 543– 553,  DOI: 10.1158/1541-7786.MCR-17-0362
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      TANKYRASE Inhibition Enhances the Antiproliferative Effect of PI3K and EGFR Inhibition, Mutually Affecting β-CATENIN and AKT Signaling in Colorectal Cancer
      Solberg, Nina T.; Waaler, Jo; Lund, Kaja; Mygland, Line; Olsen, Petter A.; Krauss, Stefan
      Molecular Cancer Research (2018), 16 (3), 543-553CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)
      Overactivation of the WNT/β-CATENIN signaling axis is a common denominator in colorectal cancer. Currently, there is no available WNT inhibitor in clin. practice. Although TANKYRASE (TNKS) inhibitors have been proposed as promising candidates, there are many colorectal cancer models that do not respond pos. to TNKS inhibition in vitro and in vivo. Therefore, a combinatorial therapeutic approach combining a TNKS inhibitor (G007-LK) with PI3K (BKM120) and EGFR (erlotinib) inhibitors in colorectal cancer was investigated. The data demonstrate that TNKS inhibition enhances the effect of PI3K and EGFR inhibition in the TNKS inhibitor-sensitive COLO320DM, and in the nonsensitive HCT-15 cell line. In both cell lines, combined TNKS/PI3K/EGFR inhibition is more effective at reducing growth than a dual TNKS/MEK inhibition. TNKS/PI3K/EGFR inhibition affected in a context-dependent manner components of the WNT/β-CATENIN, AKT/mTOR, EGFR, and RAS signaling pathways. TNKS/PI3K/EGFR inhibition also efficiently reduced growth of both COLO320DM and HCT-15 tumor xenografts in vivo. At the highest doses, tumor xenograft growth was halted without affecting the body wt. of the tested animals. Implications: Combining TNKS inhibitors with PI3K and EGFR inhibition may expand the therapeutic arsenal against colorectal cancers. Mol Cancer Res; 16(3); 543-53. ©2017 AACR.
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      Waaler, J.; Machon, O.; Tumova, L.; Dinh, H.; Korinek, V.; Wilson, S. R.; Paulsen, J. E.; Pedersen, N. M.; Eide, T. J.; Machonova, O.; Gradl, D.; Voronkov, A.; Kries, J. P.; von Krauss, S. A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice. Cancer Res. 2012, 72, 2822– 2832,  DOI: 10.1158/0008-5472.CAN-11-3336
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      51
      A Novel Tankyrase Inhibitor Decreases Canonical Wnt Signaling in Colon Carcinoma Cells and Reduces Tumor Growth in Conditional APC Mutant Mice
      Waaler, Jo; Machon, Ondrej; Tumova, Lucie; Dinh, Huyen; Korinek, Vladimir; Wilson, Steven Ray; Paulsen, Jan Erik; Pedersen, Nina Marie; Eide, Tor J.; Machonova, Olga; Gradl, Dietmar; Voronkov, Andrey; von Kries, Jens Peter; Krauss, Stefan
      Cancer Research (2012), 72 (11), 2822-2832CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      This preclin. proof-of-concept study suggests a new strategy to treat colon cancer by increasing the degrdn. of β-catenin, which drives this disease.
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      WO2019243822A1.
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      Tankyrase, a member of human PARP protein super-family, catalyzes a covalent post-translational modification of substrate proteins. This modification, poly(ADP-ribos)ylation, leads to changes in protein interactions and modifies downstream signaling events. Tankyrase 1 is a potential drug target due to its functions in telomere homeostasis and in Wnt signaling. We describe here optimization and application of an activity-based homogenous assay for tankyrase inhibitors in a high-throughput screening format. The method measures the consumption of substrate by the chem. conversion of the remaining NAD+ into a stable fluorescent condensation product. Conditions were optimized to measure the enzymic auto-modification of a recombinant catalytic fragment of tankyrase 1. The fluorescence assay is inexpensive, operationally easy and performs well according to the statistical anal. (Z'= 0.7). A validatory screen with a natural product library confirmed suitability of the assay for finding new tankyrase inhibitors. Flavone was the most potent (IC50=325 nM) hit from the natural compds. A flavone deriv., apigenin, and iso-Pr gallate showed potency on the micromolar range, but displayed over 30-fold selectivity for tankyrase over the studied isoenzymes PARP1 and PARP2. The assay is robust and will be useful for screening new tankyrase inhibitors.
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      Acta Crystallographica, Section D: Biological Crystallography (2010), 66 (2), 125-132CODEN: ABCRE6; ISSN:0907-4449. (International Union of Crystallography)
      The usage and control of recent modifications of the program package XDS for the processing of rotation images are described in the context of previous versions. New features include automatic detn. of spot size and reflecting range and recognition and assignment of crystal symmetry. Moreover, the limitations of earlier package versions on the no. of correction/scaling factors and the representation of pixel contents have been removed. Large program parts have been restructured for parallel processing so that the quality and completeness of collected data can be assessed soon after measurement.
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      Coot: model-building tools for molecular graphics
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      Acta Crystallographica, Section D: Biological Crystallography (2004), D60 (12, Pt. 1), 2126-2132CODEN: ABCRE6; ISSN:0907-4449. (Blackwell Publishing Ltd.)
      CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for x-ray structure soln., structure comparison and anal., and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as 'Coot'.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXhtVars73P&md5=1be390f3bb6fd584468499ad0921161e
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      Murshudov, G. N.; Skubák, P.; Lebedev, A. A.; Pannu, N. S.; Steiner, R. A.; Nicholls, R. A.; Winn, M. D.; Long, F.; Vagin, A. A. REFMAC5 for the Refinement of Macromolecular Crystal Structures. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2011, 67, 355– 367,  DOI: 10.1107/S0907444911001314
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      Acta Crystallographica, Section D: Biological Crystallography (2011), 67 (4), 355-367CODEN: ABCRE6; ISSN:0907-4449. (International Union of Crystallography)
      This paper describes various components of the macromol. crystallog. refinement program REFMAC5, which is distributed as part of the CCP4 suite. REFMAC5 utilizes different likelihood functions depending on the diffraction data employed (amplitudes or intensities), the presence of twinning and the availability of SAD/SIRAS exptl. diffraction data. To ensure chem. and structural integrity of the refined model, REFMAC5 offers several classes of restraints and choices of model parameterization. Reliable models at resolns. at least as low as 4 Å can be achieved thanks to low-resoln. refinement tools such as secondary-structure restraints, restraints to known homologous structures, automatic global and local NCS restraints, 'jelly-body' restraints and the use of novel long-range restraints on at. displacement parameters (ADPs) based on the Kullback-Leibler divergence. REFMAC5 addnl. offers TLS parameterization and, when high-resoln. data are available, fast refinement of anisotropic ADPs. Refinement in the presence of twinning is performed in a fully automated fashion. REFMAC5 is a flexible and highly optimized refinement package that is ideally suited for refinement across the entire resoln. spectrum encountered in macromol. crystallog.
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    • General and specific synthetic procedures and spectra for all compounds and inhibition data and crystallography; atomic coordinates and structure factors have been deposited to the Protein Data Bank under accession number 7O6X, and raw diffraction images are available at IDA (https://doi.org/10.23729/4d448eb0-c6ef-4b7d-a557-3758f5f68d47). The authors will release the atomic coordinates upon article publication (PDF)


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