ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
CONTENT TYPES

Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent

  • Kevin M. Foote
    Kevin M. Foote
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
  • J. Willem M. Nissink*
    J. Willem M. Nissink
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
    *E-mail: [email protected]
  • Thomas McGuire
    Thomas McGuire
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
  • Paul Turner
    Paul Turner
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
    More by Paul Turner
  • Sylvie Guichard
    Sylvie Guichard
    Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
  • James W. T. Yates
    James W. T. Yates
    DMPK, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
  • Alan Lau
    Alan Lau
    Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
    More by Alan Lau
  • Kevin Blades
    Kevin Blades
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
    More by Kevin Blades
  • Dan Heathcote
    Dan Heathcote
    Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
  • Rajesh Odedra
    Rajesh Odedra
    Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
  • Gary Wilkinson
    Gary Wilkinson
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
  • Zena Wilson
    Zena Wilson
    Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
    More by Zena Wilson
  • Christine M. Wood
    Christine M. Wood
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
  • , and 
  • Philip J. Jewsbury
    Philip J. Jewsbury
    Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
Cite this: J. Med. Chem. 2018, 61, 22, 9889–9907
Publication Date (Web):October 22, 2018
https://doi.org/10.1021/acs.jmedchem.8b01187

Copyright © 2018 American Chemical Society. This publication is licensed under these Terms of Use.

  • Open Access
  • Editors Choice

Article Views

22601

Altmetric

-

Citations

LEARN ABOUT THESE METRICS
PDF (6 MB)
Supporting Info (2)»

Abstract

The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.

Introduction

ARTICLE SECTIONS
Jump To

Human cells are constantly exposed to DNA-damage events as a result of environmental and endogenous factors. In order to suppress genomic instability, an integrated group of biological pathways collectively called the DNA-damage response (DDR) has evolved to recognize, signal, and promote the repair of damaged DNA. (1,2) DNA-damage leads to cell death if sufficiently high and left unrepaired and is the concept behind DDR inhibition for cancer therapy. Tumor cells are sensitized to DDR based therapies through a combination of relatively rapid proliferation and DDR pathways that may already be functionally compromised. Ataxia telangiectasia and rad3-related (ATR) is a serine/threonine-protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family of proteins and is a key regulator of DNA replication stress response (RSR) and DNA-damage activated checkpoints. (3,4) Replication stress, a hallmark of cancer, (5) may occur in tumors through oncogene drivers or induced exogenously through treatment with DNA-damaging drugs or ionizing radiation (IR). Persistent replication stress leads to DNA breaks that, if left unresolved, are highly toxic to cells. In recent years potent and selective inhibitors of ATR (Scheme 1) have been developed from orthogonal chemical series demonstrating preclinical in vivo proof of concept. These pivotal compounds and studies have been extensively reviewed (6−9) and reveal synthetic lethality of ATR inhibitors on tumors with p53-mutations or ataxia telangiectasia mutated (ATM) loss-of-function, (10,11) as well as synergy in combination with a broad range of replication stress inducing chemotherapy agents such as platinums, (12) ionizing radiation (13,14) and with novel agents such as the PARP inhibitor olaparib. (15)

Scheme 1

Scheme 1. ATR Inhibitorsa

a2, 3, and 4 are undergoing clinical testing.

We have previously described a series of potent and selective ATR inhibitors, exemplified by 1 (AZ20), from the sulfonylmethyl morpholinopyrimidine series. (16) Compound 1 and close analogues (17) were shown to inhibit the growth of ATM-deficient xenograft models at well tolerated doses. However, we did not consider compound 1 of sufficient quality for further development due to low aqueous solubility and high risk for drug–drug interactions (DDI) resulting from cytochrome P450 3A4 (CYP3A4) time-dependent inhibition (TDI). In this report we describe our further studies to identify ATR inhibitors with the requisite properties suitable for clinical development that led to the discovery of 2 (AZD6738). The sulfoximine morpholinopyrimidine 2, along with the aminopyrazine 3 (berzosertib, M-6620/VX-970), originating from Vertex and licensed to Merck KGaA, and most recently the naphthyridine 4 (BAY 1895344) from Bayer (18) have entered human studies. These compounds are being explored in early phase clinical trials as single agents and in combination with standard of care (SOC) and novel agents. (8,9)

Results

ARTICLE SECTIONS
Jump To

Compounds 1, 5, 6, 8, 9, and 10 (Table 1) and intermediates 39, 4649, 70 were prepared as described previously. (16) Compounds 7, 17, and 18 were prepared as shown in Scheme 2, and compounds 1116 were prepared as shown in Scheme 3. Intermediates 4345 were prepared starting from the dichloropyrimidine 39. Suzuki coupling with 2-cyclohexenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane led to 40, while SNAr reaction with 8-oxa-3-azabicyclo[3.2.1]octane and 3-oxa-8-azabicyclo[3.2.1]octane afforded 41 and 42, respectively, with no evidence of substitution at the 2-position. Cyclopropanation with 1,2-dibromoethane and strong base afforded 4345. The 2-arylpyrimidine test compounds were synthesized by Suzuki coupling between the 2-chloropyrimidine substrates 4348 and the corresponding boronic acid or esters which were either purchased or prepared from the corresponding aryl bromides using literature methods. (19)

Scheme 2

Scheme 2. a

aReagents. (a) Compound 40: (Ph3P)4Pd, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, Cs2CO3, 1,4-dioxane, water, rt. Compounds 41 and 42: 8-oxa-3-azabicyclo[3.2.1]octane or 3-oxa-8-azabicyclo[3.2.1]octane respectively, Et3N, DCM, rt. (b) Compound 43: 1,2-dibromoethane, NaH, DMF, 0 °C → rt. Compounds 44 and 45: 1,2-dibromoethane, 50% NaOH (aq), tetraoctylammonium bromide, DCM, rt. (c) Compound 7: (Ph3P)2PdCl2, 1H-indol-4-ylboronic acid, Na2CO3 (aq), 4:1 DME/water, microwave, 110 °C. Compounds 17 and 18: (Ph3P)4Pd, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine, Na2CO3 (aq), 1,4-dioxane, 95 °C.

Scheme 3

Scheme 3. a

aReagents. (a) Compound 11: (Ph3P)4Pd, 1H-pyrrolo[2,3-b]pyridine-4-ylboronic acid, Na2CO3 (aq), 1,4-dioxane, 90 °C. Compound 12: 1H-benzo[d]imidazol-2-amine, Na2CO3, DMA, 160 °C, microwave. Compound 13: (Ph3P)2PdCl2, 1H-pyrrolo[2,3-b]pyridine-4-ylboronic acid, Na2CO3 (aq), 4:1 DME:water, 110 °C, microwave. Compound 14: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, bis(dibenzylideneacetone)palladium(0), 4-bromo-1H-pyrrolo[2,3-c]pyridine, KOAc, bis(pinacolato)diboron, dioxane, 100 °C followed by compound 46, (Ph3P)4Pd, Na2CO3 (aq), 100 °C. Compound 15: 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium, 4-bromo-1H-pyrrolo[2,3-c]pyridine, KOAc, bis(pinacolato)diboron, dioxane, 95 °C followed by compound 47, (Ph3P)4Pd, Na2CO3 (aq), 95 °C. Compound 16: (Ph3P)4Pd, Na2CO3 (aq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine, dioxane, 95 °C.

Table 1. Morpholine and C-2 Heterocycle CYP3A4 TDI SAR
a

Uncertainty (95% confidence) for pIC50 measurements is 0.38 (2.4-fold) based on an average of two repeat occasions per compound.

b

Uncertainty (95% confidence) for pIC50 measurements is 0.7 (4.6-fold) based on at least two repeat measurements per compound. (median number of repeats across tables is 3). The data presented are from a variation of the ATR cell assay described in ref (16) (see Experimental Section). A good correlation is observed between ATR cell assay versions; N = 41 compounds from morpholinopyrimidine series. Correlation: 0.94. Mean difference: −0.084 pIC50. *Compound 1 IC50 = 0.050 μM in the earlier version reported. (16)

c

log D7.4 assay: lipophilicity was determined using the “shake-flask” method. Plated aliquots of sample are dried down, and octanol and water are added. Sample content of the phases is determined by LC/MS/MS after stirring, equilibration, and separation of phases by centrifuge. Full description of the assay can be found in the Supporting Information. An excellent correlation is observed between versions of the log D7.4 methods; N = 23 compounds from the morpholinopyrimidine series. Correlation: 0.96. Mean difference: −0.075. #Compound 1 log D7.4 = 2.7 using the earlier methodology (ref (16)). ND = not determined.

d

Mean value (N ≥ 2) unless otherwise stated. Compounds were preincubated at 10 μM with human liver microsomes (1 mg/mL) with and without NADPH (5 mM) for 30 min at 37 °C followed by 15 min incubation with 10 μM midazolam; analysis of 1-hydroxymidazolam was performed using liquid chromatography–tandem mass spectrometry. (34) No activity detected vs control for 1A2, 2C19, 2C9, and 2D6. Result for compound 12 was just above background level in test 1 and below background level (<11%) in test 2; result for test 1 shown.

1-H-Benzimidazole test compounds 1930 (Table 4) were made as shown in Schemes 4 and 5. Cyclopropanation of 49 led to 50 where reaction with 3(R)-methylmorpholine followed by sodium tungstate catalyzed oxidation of the sulfide proceeded well to afford 51 without overoxidation of the pyrimidine ring. Reaction with 1H-benzo[d]imidazol-2-amine and N-methyl-1H-benzo[d]imidazol-2-amine led directly to compounds 19 and 21, respectively; compound 19 was derivatized to the N-acetyl 20. Benzimidazoles 2230 were made starting from the 2-chloropyrimidine intermediate 47 (Scheme 5). Buchwald–Hartwig coupling with the appropriate substituted 2-nitroaniline utilizing the Xantphos ligand system afforded intermediates 5260. Reduction of nitro to amino was achieved under indium catalyzed transfer hydrogenation conditions or with zinc in acetic acid to give the corresponding anilines 6169 which were then cyclized using cyanogen bromide to afford compounds 2230.

Scheme 4

Scheme 4. a

aReagents: (a) 1,2-dibromoethane, 50% NaOH (aq), tetraoctylammonium bromide, toluene, 60 °C; (b) (R)-3-methylmorpholine, DIPEA, 1,4-dioxane, 80 °C; (c) NaO4W·2H2O, Bu4NHSO4, EtOAc, H2O2, 0 °C → rt. (d) Compound 19: 1H-benzo[d]imidazol-2-amine, Cs2CO3, DMA, 110 °C, microwave. Compound 21: N-methyl-1H-benzo[d]imidazol-2-amine, Cs2CO3, DMA, 90 °C. (e) DMAP, Ac2O, 90 °C.

Scheme 5

Scheme 5. a

aReagents: (a) substituted 2-nitroaniline, Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 80 °C, microwave; (b) Zn, AcOH, rt or In, NH4Cl (aq), EtOH, reflux; (c) cyanogen bromide, MeOH, rt.

The iodobenzyl compound 70 was used as the starting point for the synthesis of sulfoxides 31, 32, and sulfoximines 2, 3336 (Scheme 6). Displacement of the iodide in 70 with sodium thiomethoxide gave sulfide 71 in high yield which was then oxidized to the corresponding sulfoxide R/S-72 with sodium metaperiodate. Compounds were either made as a mixture of diastereoisomers and separated by chiral chromatography or prepared starting with the appropriate chirally pure sulfoxide. The mixture of sulfoxide diastereoisomers R/S-72 was readily separable by chiral chromatography or vapor diffusion crystallization to afford R-72 as a white crystalline solid and S-72 as an oil. The stereochemistry of R-72 was confirmed by X-ray structure (Supporting Information Figure S2). Later, a biocatalytic process to the chiral sulfoxide R-72 was developed from 71 on large scale. (20) Cyclopropanation led to R/S-73 followed by Suzuki coupling to afford the test compounds 31 and 32. The sulfoximine moiety was introduced starting from the sulfoxides via rhodium catalyzed nitrene insertion. (21) This proceeded with complete retention of stereochemistry and worked equally well starting either from the mixture of sulfoxide diastereoisomers to afford R/S-74 or from single diastereoisomer R-72 to afford R-74. Cyclopropanation resulted in rapid removal of the trifluoroamide group to give R/S-75, followed by Suzuki reaction that led to test compounds 2, 33, and 34 or reaction with N-methylbenzo[d]imidazole-2-amine that led to 35 and 36.

Scheme 6

Scheme 6. a

aReagents: (a) NaSMe, DMF, rt; (b) NaIO4, EtOAc, MeOH, H2O, rt; (c) 1,2-dibromoethane, 50% NaOH (aq), tetraoctylammonium bromide, 2-Me-THF, 60 °C; (d) X-Phos second generation precatalyst, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, Cs2CO3, 1,4-dioxane/H2O (4:1), 90 °C; (e) trifluoroacetamide, iodobenzene diacetate, Rh(OAc)2 dimer, MgO, isopropylacetate, 80 °C; then 7 M NH3 in MeOH, rt; (f) NaOH (50% aq), 1,2-dibromoethane, tetraoctylammonium bromide, mTHF, rt. (g) Compound 33: (Ph3P)2PdCl2, 2 M Na2CO3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, DME/H2O (4:1), 90 °C, then 2 M NaOH (aq), 50 °C. Compound 34: 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid, (Ph3P)2PdCl2, 2 M Na2CO3, DME/H2O (4:1), 90 °C. Compounds 35 and 36: Cs2CO3, N-methyl-1H-benzo[d]imidazol-2-amine, DMA, 80 °C.

Discussion

ARTICLE SECTIONS
Jump To

Compound 1 is a potent ATR inhibitor with excellent kinase selectivity and free exposure and is a useful tool compound to explore ATR pharmacology in vivo. (16) However, compound 1 was also found to be a time-dependent inhibitor of CYP3A4 and to suffer from low aqueous solubility. Inhibition of CYP3A4, particularly mechanism based inhibition, is a concern for clinical DDI, (22−24) whereas low solubility limits the maximum absorbable dose (Dabs). (25) These properties increase risk of failure in clinical development, and compound 1 was therefore not considered a suitable candidate for clinical-enabling studies. Eliminating CYP3A4 TDI and achieving high aqueous solubility while at the same time maintaining high ATR potency, excellent specificity, and the attractive pharmacokinetic properties exhibited by 1 were the key medicinal-chemistry design goals in the optimization phase.
CYP TDI has been observed as a common feature in kinase inhibitors with CYP3A4 being the most commonly inhibited isoform. (26) CYP TDI is associated with the formation of covalent (or reversible-covalent) adducts to heme or protein following metabolic activation. (23,24) In addition to the risk of DDIs, formation of reactive metabolites is a causative factor for idiosyncratic drug toxicity. (23,27) The risk and impact of clinical DDI will be determined by overall drug disposition, dose, regimen, and target patient population. While compound 1 clearly demonstrated TDI of CYP3A4 when incubated at 10 μM in human microsomes, (16) we did not fully characterize this activity or model in detail the human PK and predicted clinical dose to understand the magnitude of the expected clinical DDI. We anticipated ATR inhibitors would be combined with cytotoxic and targeted drugs in the clinic. As DDI arising from inhibition of CYP3A4 would complicate co-dosing of such agents and many likely co-medicants, (28) we set out to remove this undesirable activity.
The indole and morpholine groups were thought particularly vulnerable to metabolic activation. The susceptibility of cyclic tertiary amines such as morpholine to α-carbon oxidation, generating reactive iminium ion intermediates, is well described. (29−31) Indoles are known to undergo ring hydroxylation particularly at C-5 and/or C-6 positions; (32) these species could arise via reactive epoxides and could also lead to quinone-like reactive intermediates following additional bioactivation. Oxidation of indole has also been observed at C-2 or C-3, presumably via the corresponding epoxide, and further oxidation and/or oxidative ring cleavage can lead to anthranilic acid products. The putative metabolic vulnerability of morpholine and indole presented us with a potentially insoluble problem as our previous work clearly demonstrated the importance of both groups to ATR potency. (16)
Reactive metabolites formed from bioactivation are generally electrophilic in character and highly unstable. Trapping experiments can be used to detect and characterize metabolites whereby a compound is incubated in human liver microsomal preparations and any reactive metabolites generated are trapped by specific added nucleophiles. Orthogonal nucleophiles are used to trap the different electrophilic species arising from bioactivation of chemical substrates. The nucleophiles commonly used are glutathione (GSH), a soft nucleophile efficient at trapping soft electrophiles such as epoxides, cyanide to trap iminium species arising from oxidation of tertiary amines and methoxyamine to effectively trap aldehyde products as Schiff bases. (33) These screens provide valuable mechanistic information to support rational medicinal chemistry design. When 1 was incubated with human liver microsomes, adducts with GSH but not cyanide were detected. While the mechanisms of bioactivation and TDI may not necessarily overlay, the formation of GSH adducts implicates the indole group, likely through ring oxidation.
We had systematically explored the structure–activity relationships (SARs) in the morpholinopyrimidine pharmacophore, varying each of the substituents on the pyrimidine core. These compounds now allowed facile investigation into the molecular features in 1 responsible for CYP3A4 TDI, independent of ATR potency.
The unsubstituted and 3(R)-methyl substituted morpholines (compounds 5 and 1, respectively) both show clear CYP3A4 TDI activity when incubated at 10 μM in human liver microsomes using a standard liquid chromatography–tandem mass spectrometric end point (Table 1). (34) Introducing structural architecture to eliminate reactive moieties resulting from oxidation on the morpholine ring, for example, by modification of the methylene adjacent to the oxygen atom using the bridged morpholine 6 or removal of the nitrogen heteroatom by substitution of morpholine for the 3,6-dihydro-2H-pyran 7, did not eliminate CYP3A4 TDI activity compared with morpholine. The dihydropyran and bridged morpholines, both of which have been described as morpholine isosteres in mTOR inhibitor series, (35,36) are equivalent in ATR potency to unsubstituted morpholine but at the price of higher lipophilicity. The impact of blocking and/or deactivating substituents on the indole ring was investigated. Simple ring substituents that retain ATR potency, for example, the 6-fluoroindole 8, did not reduce CYP3A4 TDI. In contrast, addition of a polar and deactivating group such as acetamido 9 and replacement of the indole, for example, with benzimidazole 10, which has equivalent lipophilicity to the indole 5, led to undetectable CYP3A4 TDI activity. In both cases ATR potency was also significantly reduced but these results supported the notion that the indole ring was the likely key contributor to CYP3A4 TDI. We discovered the 7-azaindole (1H-pyrrolo[2,3-b]pyridine) 11 retains the ATR potency of the indole while effectively eliminating CYP3A4 TDI. In addition, through a wider campaign to identify ATR-active indole isosteres, the 2-amino-N1-substituted benzimidazole 12 was found to have no or weak detectable 3A4 TDI. This variant was also found to possess superior cellular potency without increasing lipophilicity compared with the indole 5. Unknown to us at the time, Safina et al. (37) had developed a series of PI3Kδ-specific morpholinopyrimidines substituted with 4-indole that were also found to be potent CYP3A4 TDIs and further determined that the 4-indole group was associated with this activity. In contrast to our own findings, replacement of the indole with 7-azaindole in the PI3Kδ series did not attenuate CYP3A4 TDI. The apparent conflicting results are a reminder that metabolic activation is complex, and SAR may not be simplified to contributions of individual functional groups. It is whole-molecule structure and properties that determine metabolic fate. However, in our efforts toward identifying an ATR inhibitor candidate for human studies, both the 7-azaindole 11 and 2-aminobenzimidazole 12 became productive leads for optimization.
In the 7-azaindole series, the SAR was found to mirror that determined for indole with cellular potency increasing for the corresponding 3-(R)-methylmorpholine 13 (Table 2). Pleasingly we could not detect CYP3A4 TDI activity for this compound. Measured lipophilicity for 13 is unchanged in comparison to 1, and unsurprisingly solubility remains low.
Table 2. Azaindole SAR
a

Uncertainty (95% confidence) for pIC50 measurements is 0.38 (2.4-fold) based on an average of two repeat occasions per compound.

b

Uncertainty (95% confidence) for pIC50 measurements is 0.7 (4.6-fold) based on at least two repeat measurements per compound.

c

Lipophilicity ligand efficiency (LLE): ATR cell pIC50 – log D7.4.

d

Solid material was agitated in 0.1 M pH 7.4 phosphate buffer for 24 h, double centrifuged, and the supernatant analyzed for compound concentration by LC–UV–MS. Crystallinity was assessed by polarized light microscopy of remaining solid. Full description is provided in Supporting Information. Lowest solubility given in the table where multiple measurements were taken: N ≥ 3 for compounds 1, 13, 15; N = 1 for compounds 14, 16, 17, 18. ND: not determined.

Substitution with the 6-azaindole (1H-pyrrolo[2,3-c]pyridine) isomer surprisingly resulted in compounds with much improved cellular potency compared with the corresponding indole and 7-azaindole. Moreover the 6-azaindole series combines improved potency with reduced lipophilicity and improved aqueous solubility (compounds 1418, Table 2; note that the very high solubility result for compound 17 is most likely an outlier that we speculate is due to low crystallinity) while also having no detectable CYP3A4 TDI. It is interesting to observe a seemingly small structural change delivering such a significant effect on both potency and physicochemical properties. (38) Directionality of the hydrogen bond acceptor nitrogen in the azaindole isomers is changed relative to the morpholine hinge binder offering the potential to impact key interactions to the protein. Recent structures of ATR-mimicking PI3K mutants, (39) and an ATR cryo-EM (40) structure, suggest that the difference in potency between the azaindoles isomers can be explained by their interaction with Asp2335, potentially mediated by a water molecule. 6-Azaindole is also considerably more basic than 7-azaindole (pKa of 7.9 and 4.6, respectively (41)) resulting in an expected change in ionization state at physiological pH and concomitant effects on log D7.4 and solubility. The unsubstituted morpholine 7-azaindole 14 demonstrated excellent ATR cellular potency (IC50 < 100 nM) and again the established morpholine SAR translated, with a significant increase in potency observed when 3-(R)-methylmorpholine was employed over the 3-(S) methyl isomer (compounds 15 and 16, respectively). The bridged morpholines, compounds 17 and 18, retained potency compared to morpholine 14, and the reduced lipophilicity provided by the 6-azaindole group led to compounds with a good overall balance of properties. It is noticeable from the compounds shown in Table 2 that the hitherto excellent ATR enzyme to cell correlation breaks down. We had high confidence in the cellular assay measuring inhibition of CHK1 phosphorylation, a direct substrate of ATR, in response to a DNA-damage stimulus. Presumably, with the more potent compounds, the IC50 is below the detection threshold (tight binding limit) of the enzyme assay. Therefore, at this stage of the optimization phase the cellular assay was primarily used to drive chemistry in conjunction with lipophilicity and physicochemical driven properties of aqueous solubility, permeability, and metabolic stability. The 3-(R)-methylmorpholine 6-azaindole 15 stood out in combining excellent cellular potency and moderate lipophilicity (LLE = 5.8) with improved aqueous solubility and no measurable CYP3A4 TDI and represented a significant advancement over the indole lead 1.
The benzimidazole head group utilized in compound 12, substituted at the 2-position with amino or alkyl substituents on a morpholinopyrimidine core, was described in a series of antitumor agents with PI3K activity from Zenyaku Kogyo. (42) We discovered the novel methylsulfonylmethyl morpholinopyrimidine 12 to possess excellent ATR potency (Table 1) albeit with some class 1 PI3K inhibitory activity (e.g., PI3Kα IC50 = 0.24 μM). Substitution on the morpholine hinge binder has been shown to affect PI3K activity; (16,36) thus the 3(R)-methylmorpholine 2-aminobenzimidazole (compound 19, Table 3) became a key compound to make that was subsequently shown to possess greatly improved ATR potency and selectivity over PI3Kα (ATR cell IC50 = 0.015 μM, PI3Kα IC50 = 9 μM).
Table 3. Benzimidazole C2 SAR
CompoundR1ATR IC50 (μM)aATR cell IC50 (μM)blog D7.4LLESolubility, pH 7.4 (μM)cCYP3A4,% TDI, 10 μM
19H0.0010.0152.55.32020
20Ac0.0140.0171.86.07<17
21Me0.0020.0082.85.349<18
a

Uncertainty (95% confidence) for pIC50 measurements is 0.38 (2.4-fold) based on an average of two repeat occasions per compound.

b

Uncertainty (95% confidence) for pIC50 measurements is 0.7 (4.6-fold) based on at least two repeat measurements per compound.

c

Lowest solubility result is given in the table where multiple measurements were taken: N = 2 for compound 21; N = 1 for compounds 19, 20. Result for compound 19 was just above background level in test 1 and below background level (<17%) in test 2; result shown for test 1.

The potency improvement relative to indole is achieved without increasing lipophilicity; compound 19 shows borderline CYP3A4 TDI, and aqueous solubility is not significantly improved compared to indole 1. Substitution on the amino group with acetyl (compound 20) or methyl (compound 21) was well tolerated with no loss of cellular potency and in the case of the N-acetyl 20 led to higher LLE. Moreover, we did not detect CYP3A4 TDI for either of the substituted 2-aminobenzimidazole compounds. While a relatively modest improvement in aqueous solubility was perhaps evident, particularly for N-methyl 21, aqueous solubility was not robustly improved compared with indole.
Substitution on the benzimidazole aryl ring was explored for effects on potency and to address a theoretical concern that the naked aryl ring might be susceptible to metabolic instability. The result of systematic substitution on the aryl ring of the benzimidazole group with fluorine is shown in Table 4.
Table 4. Benzimidazole ring SAR
CompoundR1ATR, IC50 (μM)aATR cell, IC50 (μM)b
19H0.0010.015
224-F0.0100.13
235-F0.0020.035
246-F0.0080.12
257-F0.0905.1
264-Cl0.0175.3
274-OMe0.275.3
285-Cl0.0210.87
295-CN4.0>30
305-OMe0.5515
a

Uncertainty (95% confidence) for pIC50 measurements is 0.38 (2.4-fold). Repeat measurements: N = 2 for compound 19; N = 1 for compounds 2230.

b

Uncertainty (95% confidence) for pIC50 measurements is 0.7 (4.6-fold) based on at least two repeat measurements per compound. Repeat measurements: N = 2 for compound 19; N = 1 for compounds 2230.

A 5-F substituent (compound 23) retains the same level of ATR potency compared with unsubstituted benzimidazole 19. While 4-F and 6-F (compounds 22 and 24, respectively) retain a degree of ATR potency, the 7-F analogue (compound 25) is significantly less potent. A broader range of substituents in positions 4 and 5 (exemplified by compounds 2630, Table 4) were then made to probe into the protein further, but for all these examples reduced ATR potency was seen.
In the solid state, methylsulfone compounds such as 1 display a centrosymmetric methylsulfone to methylsulfone contact (in addition to ring–ring stacking and a hydrogen bonding network between indole N–H and sulfone oxygen) associated with high melting points and low solubility. (16) Our SAR study of the indole series demonstrated that specific changes around the methylsulfonyl moiety (e.g., addition of charged substituents) could improve physicochemical properties, but these changes ultimately led to reduced potency and/or attenuation of other fundamental properties such as permeability leading to low oral exposure. However, we had yet to attempt specific changes to the sulfone group, for example, replacement with sulfoxide or sulfoximine whereby one of the oxygen atoms is replaced with nitrogen. We hypothesized that such changes could disrupt the observed solid-state contacts albeit at the complication of introducing additional chirality and with uncertain impact on target potency.
The diastereomeric sulfoxides in the 7-azaindole series, compounds 31 and 32 (Table 5), were found to retain ATR potency compared with the corresponding sulfone 13 with no change in measured lipophilicity. These sulfoxides were also found to have high aqueous solubility though it proved challenging to generate stable crystalline forms, and therefore the apparent improvement compared with the corresponding sulfones was treated with caution. The sulfoxides are highly permeable and have high exposure from oral doses in rodents. However, the sulfoxide group is prone to oxidation in vivo and a significant level of the corresponding sulfone was observed in rodent PK studies; for this reason, despite other properties being generally attractive, we discounted the sulfoxides from further progression. The sulfoximines (compounds 2, 3336, Table 5) achieved both of the key aims we set at the start of the lead optimization campaign. The R-stereochemistry of the sulfoximine 2 was initially inferred from the stereochemistry of the sulfoxide precursor, with imination to the sulfoximine proceeding with retention of configuration, and later confirmed from an X-ray structure (Figure 1). Interestingly, hydrogen bonds are observed only between the azaindole substituents of adjacent molecules for 2, whereas the indole NH donor in the structure of 1 does not form a hydrogen bond. The centrosymmetric packing characteristic for methylsulfones as seen for 1 is prevented in the structure of 2 by introduction of the sulfoximine (Figure 1).
Table 5. Sulfoxide and Sulfoximine SAR
a

Uncertainty (95% confidence) for pIC50 measurements is 0.38 (2.4-fold) based on an average of two repeat occasions per compound.

b

Uncertainty (95% confidence) for pIC50 measurements is 0.7 (4.6-fold) based on at least two repeat measurements per compound. ND = not determined.

c

Lowest solubility result is given in the table where multiple measurements were taken: N ≥ 2 for compound 13, 2, 33, 35; N = 1 for compounds 31, 32, 34, 36.

Figure 1

Figure 1. Small-molecule crystal structures of 1 and 2. Short contacts of sulfonomethyl (left-hand panel) and azaindole (right-hand panel) moieties are indicated by dotted lines.

The R-isomer of the sulfoximine group showed slight but consistent greater potency than the corresponding S-isomer (compare 2 with 33, Table 5) and similar magnitude compared with the corresponding sulfone. The sulfoximines also benefit from a significant reduction in lipophilicity and greatly improved aqueous solubility compared to the sulfones. Data from molecular matched pairs clearly show consistent retention of ATR cellular potency for the R-isomer, concomitant reduction in lipophilicity, and improved solubility of sulfoximine analogues compared with the corresponding sulfones (Figure 2). While the sulfoximine shows a different solid-state structure, the melting point of sulfoximine 2 was measured at 222 °C and is similar to sulfone 1 (204 °C). Therefore, the observed improvement in solubility appears to be driven mainly through reduced lipophilicity, though we speculate that solvation and the removal of the methylsulfones’ centrosymmetric organization may contribute additional effects that are difficult to quantify. Replacement of methylsulfones has been shown to improve solubility in other contexts, (43) and sulfoximines may have wider utility in such cases. A further lipophilicity-related benefit of the sulfoximine group was realized in reduced hERG activity and was particularly advantageous for the 2-N-methylaminobenzimidazole analogues 35 and 36 (Figure 2). Several reviews on the properties of the sulfoximine moiety in drug discovery have since appeared elsewhere which observe the same broad trends as described here. (44−46)

Figure 2

Figure 2. Sulfone and sulfoximine matched-pairs: (a, upper-left) ATR cell pIC50; (b, upper-right) log D7.4; (c, lower-left) hERG pIC50; (d, lower-right) aqueous solubility. Numbers refer to the compounds shown in Tables 25.

Compounds that addressed the dual risks of low solubility and CYP3A4 TDI activity were further characterized as a short list to identify a candidate molecule for clinical-enabling studies. Physicochemical and ADME properties of compounds 2, 15, 21, and 35 are presented in Table 6.
Table 6. Physicochemical and ADME Characterization for Preclinical Candidate Short List Compared with Lead 1
 12152135
log D7.42.51.92.12.82.1
solubility, pH 7.4 (μM)a1066110849>780
PPB mouse, hu (% free)b14, 9.254, 2648, 264.4, 2.215, 4.3
CYP3A4 IC50 (μM)c>10>10>10>10>10
CYP3A4 %TDI, 10 μM50<20<20<18<20
hERG IC50 (μM)d50166154.615
Caco-2 Papp(A–B) (pH 6.5, 7.4)e23, 376.8, 128, ––, 53–, 8
rat, hu CLintf25, <3<3.5, <310, <325, <311, <3
rat AUC (μM·h)g1.00.80.080.40.35
a

Lowest solubility result is given in the table where multiple measurements were taken: N = 5 for compound 1, N = 3 for compound 15, N = 2 for compound 21, N = 7 for compound 2; N = 2 for compound 35.

b

Measured in 10% plasma; % free calculated for 100% plasma assuming a single-site binding model.

c

>10 μM against 1A2, 2C19, 2C9, and 2D6.

d

Average activity against the human ether-a-go-go-related gene (hERG) encoded potassium channel was determined using automated whole-cell electrophysiology. (47)

e

Median A to B Papp (1 × 10–6 cm/s), 10 μM compound concentration.

f

Median CLint: intrinsic clearance from hepatocytes (μL/min per 1 × 106 cells, 1 μM compound concentration).

g

Plasma exposure; data normalized to 1 μmol/kg; compounds were dosed orally to male Han–Wistar rats at either 4 (compounds 1 and 15) or 10 (compounds 21, 2, and 35) μmol/kg formulated in propylene glycol; compounds 1, 2, 15, 35 were dosed as solutions, and compound 21 was dosed as a suspension. The most potent of three measurements is shown.

All compounds have equivalent or improved cellular potency combined in most cases with reduced lipophilicity relative to the lead 1. The sulfoximines in particular have very high aqueous solubility, high unbound fraction, and none of this set of compounds exhibited CYP3A4 reversible inhibitory or TDI activity against the five major human P450 isoforms. The benzimidazole sulfone 21 has the highest lipophilicity and hERG potency. Employment of the sulfoximine group effectively reduces lipophilicity and hERG potency (compare sulfoximine 35 with the sulfone 21) but without impact on ATR cellular potency. All compounds exhibited high metabolic stability in human hepatocytes. The 6-azaindole sulfone (compound 15) and sulfoximine compounds in general tend to have lower permeability compared with indole and sulfones respectively, presumably as a result of more hydrophilic character and, in the case of the sulfoximines, the introduction of an additional strong hydrogen bond donor. However, permeability of all compounds measured in Caco-2 cells was high and each of the compounds had favorable free exposure relative to potency in rats. The 6-azaindole sulfone 15 has the lowest total AUC. However, this is negated by a high free fraction and high cellular potency. In comparison, the sulfoximine 2 has high total exposure combined with high unbound fraction that results in very high unbound exposure.
Kinase biochemical screening at a concentration of 1 μM suggests a high level of selectivity for these optimized morpholinopyrimidine ATR inhibitors. Kinome selectivity is depicted in Figure 3 for sulfoximine 2 (the graphs for 2-aminobenzimidazole sulfone 21 and 6-azaindole sulfone 15 in comparison to the aminopyrazine 3 can be found in the Supporting Information Figure S1). Compound 2 showed excellent selectivity, with inhibition of ∼60% for PIK3C2G and CLK4 (at 1 μM) and <50% inhibition for the remaining 407 kinases tested (data supplied in Supporting Information). The PI3K and PIKK-family specificity for the morpholinopyrimidine ATR inhibitors is shown in Table 7.

Figure 3

Figure 3. Kinome selectivity depiction for compound 2. Inhibition data (%) are shown for a compound test concentration of 1 μM. PI3K isoforms are indicated as α, β, γ, δ. Data are in Supporting Information, Table T1.

Table 7. PI3K, PIKK-Family Selectivity and Growth Inhibitory Potency for Preclinical Candidate Short List Compared with Lead 1
 12152135
ATR cell IC50 (μM)a0.0610.0740.0120.0080.009
mTOR IC50 (μM)b0.0380.370.0340.0520.15
mTOR cell: AKT pS473 IC50 (μM)c2.4>231.44.09.8
mTOR cell: p70S6K S235/236 IC50 (μM)d0.725.70.271.53.1
PI3Kα cell IC50 (μM)e>30>30>300.30>30
ATM cell IC50 (μM)f>30>30>30>30>30
DNA-PK cell IC50 (μM)g>30>30>30>30>30
LoVo GI50 (μM)h0.200.440.0560.100.25
HT29 GI50 (μM)h0.972.60.310.551.2
a

Uncertainty (95% confidence) for pIC50 measurements is 0.38 (2.4-fold) based on an average of two repeat occasions per compound.

b

Standard error of mean (SEM) pIC50 measurement is ≤0.13.

c

Inhibition of AKT pSer473 in MDA-MB-468 cells.

d

Inhibition of p70S6K pSer235/236 in MDA-MB-468 cells.

e

Inhibition of pAKT T308 in BT-474 cells.

f

Inhibition of ATM Ser1981 in HT-29 cells following IR treatment.

g

Inhibition of DNA-PK pSer2056 in HT-29 cells following IR treatment.

h

MTS (tetrazolium dye) assay with 72 h continuous exposure to compounds.

The 2-aminobenzimidazole 21 and 6-azaindole sulfone 15 also display excellent selectivity over all kinase classes but have a degree of promiscuity versus lipid kinases. It is interesting to compare kinase selectivity with the aminopyrazine 3 which exhibits a wholly different profile, something that is not unexpected given that it belongs to a different structural class (see Supporting Information Figure S1). The aminopyrazine 3 has been reported to have high ATR specificity particularly over the closely related mTOR. (48) The morpholinopyrimidine inhibitors were also screened specifically for inhibition of the related targets mTOR, PI3Kα, ATM, and DNA-PK. These compounds all show moderate inhibitory potency, relative to ATR, against mTOR in an enzyme assay and some activity in cell assays reading out mTORC1 (inhibition of AKT pSer473) and mTORC2 (inhibition of p70S6K pSer235/236). This is unsurprising as the PI3K and PIKK kinases are known to have similar binding sites, with some compounds such as NVP-BEZ235, (6) exhibiting a promiscuous pan-PI3K and -PIKK profile. In terms of protein sequence similarity, mTOR and ATM are nearest neighbors of ATR, yet a margin of activity was observed in all cases including mTOR, relative to inhibition of ATR-dependent kinase signaling. Moreover, no activity could be detected for PI3Kα, ATM, or DNA-PK in cell-based systems. These combined data suggest the optimized compounds are unlikely to have activity against other PI3K/PIKK signaling pathways at relevant doses. LoVo are MRE11A mutant (MRE11A is key component of the ATM signaling and DNA double-strand break (DSB) repair pathway) colorectal adenocarcinoma cells which are sensitive to ATR inhibitors. (16) Compound 1 was shown to induce S-phase arrest, an increase in γH2AX over time, and caspase-3 activation and cell death. (49) HT29 colorectal adenocarcinoma cells are classified as MRE11A and ATM-proficient expressing high levels of total ATM protein without an ATM pathway defect and therefore expected to be relatively insensitive to selective ATR inhibition. As can be seen in Table 7, the morpholinopyrimidine ATR inhibitors show greater growth inhibition in LoVo compared with HT29 in support of this general hypothesis. Across a broader cell panel, ATR inhibitors from structurally orthogonal series show an inhibition profile that is distinct from PI3K and PIKK-family inhibitors, further supporting a cellular mode of action arising from selective ATR inhibition (Figure 4).

Figure 4

Figure 4. Colon and gastric tumor cell line responses for ATR inhibitors 1, 2, 3 compared with NVPBEZ-235 (labeled pPI3/mTORi) (6) (mTOR, PI3K, ATR, ATM, DNA-PK), AZD8186 (50) (labeled PI3Kβ+δ), and AZD8835 (51) (labeled PI3Kα+δ). Data shown are normalized as pGI50 minus mean pGI50 across the panel to correct for the influence of absolute potency. Hierarchical clustering of profiles is shown on the right.

The compounds were next characterized for tumor growth inhibition (TGI) in vivo. Compounds were first administered at their maximum well-tolerated daily dose by oral gavage to female nude mice bearing human LoVo colorectal adenocarcinoma xenografts. Mouse tolerance of the morpholinopyrimidine ATR inhibitors was found to be variable. Indole sulfone 1 and the sulfoximines 2 and 35 were well tolerated at 50 mg/kg once daily (QD), whereas the 6-azaindole sulfone 15 and 2-methylaminobenzimidazole sulfone 21 were tolerated at a maximum daily dose of 25 mg/kg QD. From a mechanistic standpoint and as a monotherapy, we expected continuous exposure would be required to drive efficacy. (16) A broad relationship can be seen between the observed tolerance, efficacy, and compound exposure in mouse relative to potency.
All compounds other than compound 35, achieved TGI > 50% in the LoVo model when dosed once daily over the course of the study (Table 8). The comparative lack of efficacy for compound 35 can be explained by its lowest free plasma concentration multiple over LoVo GI50 measured at 8 h of all the compounds tested (Table 9). The 7-azaindole sulfoximine 2 showed the greatest TGI, equivalent or greater at 50 mg/kg across multiple experiments, to the indole sulfone lead 1, and this is associated with free plasma concentration at 8 h in excess of the LoVo GI50. The total plasma concentration of the 6-azaindole sulfone 15 was found to be the lowest of the compounds tested, but the combination of high unbound fraction with high potency results in a high free plasma multiple over LoVo GI50. In contrast, benzimidazole sulfone 21 shows high total drug plasma concentration and high potency but has a relatively high bound fraction, particularly in comparison to compounds 2 and 15, and this leads to a free plasma multiple over LoVo GI50 in a similar range to the other compounds. Twice-daily dosing was investigated for compounds 1, 2, and 15 in an attempt to achieve longer exposure and drive a greater tumor response. When the maximum well-tolerated daily single dose was split (dosed 8 h apart), neither compound 15 or 1 showed greater antitumor activity. For indole sulfone 1, this may be explained by a relatively flat PK profile in the mouse negating the impact of twice daily dosing (BD). (16) The 6-azaindole sulfone 15 has a relatively short half-life in mouse, and we expected BD dosing would lead to greater efficacy. However, the efficacy achieved for compound 15 dosed BD was indistinguishable from the higher single dose. In contrast, 7-azaindole sulfoximine 2 achieved near complete TGI in the LoVo xenograft model when administered at a dose of 25 mg/kg BD. The time each day that free concentrations in plasma were above the in vitro LoVo GI50 was estimated using the observed plasma concentrations following a single dose of each compound. This duration exhibits a saturating relationship with tumor growth inhibition (Figure 5). The relationship is consistent across compounds regardless of differences in pharmacokinetic properties, including different terminal half-lives in the mouse. This analysis broadly correlates with the cover seen in earlier experiments, with 15 showing the largest difference. A clear dose–response could be demonstrated for 2 in LoVo (Table 8 and Figure 6, top graph), and this was compared with HT29 (Figure 6, bottom graph). Compound 2 delivers significant TGI in LoVo at doses as low as 25 mg/kg QD or 12.5 mg/kg BD. A dose of 75 mg/kg QD leads to regression in the LoVo model albeit tolerability is borderline with 4 of 10 animals in the group terminated in accord with study protocol due to bodyweight loss greater than 15%. In the remaining six animals a maximum bodyweight loss of 9% was observed. Therefore, 75 mg/kg, while formerly tolerated, was not considered to be a well-tolerated dose. The observed in vitro sensitivity (Table 7) translated in vivo with no significant antitumor efficacy observed for 2 in HT29 using doses and schedules which are highly active in LoVo xenografts (Figure 6, bottom graph). γH2AX is a sensitive marker for DNA damage and a useful marker to study ATR inhibition. Increases in γH2AX reflect the time-dependent accumulation of collapsed replication forks, which only occur in actively replicating cells during S-phase of the cell cycle, and replication-associated DSBs. (52,53) In LoVo xenografts, the magnitude and maintenance of γH2AX over 24 h are obtained in a dose-dependent manner after repeat daily dosing with the sulfoximine 2 (Figure 7), and this is associated with the greater antitumor effect observed for this compound. We observe an indirect relationship between plasma PK and tumor PD based on γH2AX induction, with signals being sustained beyond 24 h despite plasma concentrations predicted to be below detectable levels at this time point (LOQ 0.09 μM data not shown). While we need sufficient levels and duration of cover to induce DNA breaks and γH2AX, once these have formed, it may take many hours for the damage to be repaired, or cells to die, and the γH2AX signal to dissipate. Persistence of γH2AX signal over time (after the damage insult) is indicative of unrepaired DSBs and/or DNA repair inhibition and is observed even after breaks have been repaired. (52)
Table 8. Monotherapy in Vivo Tumor Growth Inhibition (TGI) in Human LoVo Colorectal Adenocarcinoma Xenografts
CompoundDose (mg/kg)ScheduleTGIa (p-value t test vs vehicle control)
150QD, 20 d88 (p < 0.0005)
 50QD, 14 d67 (p < 0.0005)
 50QD, 13 d77 (p < 0.0005)
 25BD, 13 d78 (p < 0.0005)
275QD, 11 d>100 (p < 0.0005)
 50QD, 14 d72 (p < 0.0005)
 50QD, 13 d81 (p < 0.0005)
 50QD, 15 d89 (p < 0.0005)
 25QD, 15 d38 (p < 0.049)
 25QD, 11 d45 (p < 0.002)
 10QD, 15 d7 (p ns)
 25BD, 13 d96 (p < 0.0005)
 12.5BD, 11 d45 (p < 0.0002)
1525QD, 20 d60 (p < 0.0005)
 25QD, 13 d59 (p < 0.0005)
 12.5BD, 13 d62 (p < 0.0005)
2125QD, 20 d67 (p < 0.0005)
3550QD, 14 d27 (p < 0.05)
a

Female nude mice bearing established human LoVo xenografts were dosed orally with compound at the indicated dose and schedule. ns = not significant.

Table 9. Plasma Concentration at 8 h after Multiple Doses in Nude Mouse up to Compound Maximum Well Tolerated Dose
CompoundDose (mg/kg)Dosing frequencyMean 8 h plasma concn, μM (Std Dev)aFree plasma LoVo multiple
150QD3.5 (1.2)2.5
 25BD1.8 (0.62)1
275QD2.6 (2.0)3
 50QD2.2 (0.52)3
 25BD0.74 (0.58)1
1525QD0.78 (0.62)6.5
 12.5BD0.22 (0.20)2
2125QD8.3 (1.3)3.5
3550QD0.94 (0.39)0.5
a

Female nude mice bearing established human LoVo colorectal adenocarcinoma xenografts were dosed orally with compounds either once-daily (QD) [compound 1, averaged data from 3 {N = 10, mean = 4.2 μM (Std Dev = 1.3)}, 4 {N = 10, 3.1 (1.1)}, and 14 {N = 10, 3.2 (0.77)} consecutive doses; compound 2, 75 mg/kg, averaged data from 4 doses; 50 mg/kg, averaged data from 4 {N = 5, 2.1 (0.65)} and 14 {N = 10, 2.3 (0.49)}, consecutive doses; compound 15, 4 consecutive doses (N = 10 independent samples); compound 21, 4 consecutive doses (N = 5 independent samples); compound 35, 14 consecutive doses (N = 10 independent samples)] or twice-daily for 8 consecutive doses. Plasma was sampled at 8 h following the last dose.

Figure 5

Figure 5. Exposure of ATR inhibitors 1, 2, 15, 21, and 35 is correlated to tumor growth inhibition (TGI). The observed plasma concentrations following a single dose of each compound were multiplied by the compound specific in vitro measured free fraction and divided by in vitro GI50 to give fold free concentration above GI50. The time above in vitro LoVo GI50 is plotted against LoVo xenograft tumor growth inhibition in vivo. A logarithmic trendline (Log.(All)) best-fit curve is shown for all compounds.

Figure 6

Figure 6. In vivo tumor growth inhibition (TGI) for compound 2. Top graph: Female nude mice bearing established human LoVo (MRE11A mutant/ATM deficient) colorectal adenocarcinoma xenografts were dosed orally with either vehicle (◆) or 2 at 10 mg/kg once daily (×, day 22 TGI = 7%, p = ns), 25 mg/kg once daily (■, day 22 TGI = 38%, p < 0.049), 50 mg/kg once daily (△, day 22 TGI = 89%, p < 0.0005). Bottom graph: Female nude mice bearing established HT-29 (MRE11A wild type/ATM-proficient) colorectal adenocarcinoma xenografts were dosed orally with either vehicle (◆) or 2 at 25 mg/kg twice daily (●, day 27 TGI = 5%, p = ns), 50 mg/kg once daily (△, day 27 TGI = 10%, p = ns) or 75 mg/kg once daily (□, day 27 TGI = 30%, p < 0.005); ns = not significant.

Figure 7

Figure 7. Compound 2 γH2AX DNA-damage biomarker pharmacodynamics in established LoVo tumor xenografts in female nude mice. Mice were dosed with either vehicle or 2 at 10 mg/kg, 25 mg/kg, 50 mg/kg, or 75 mg/kg once daily for 4 consecutive days before tissue sampling at 8 or 24 h after the fourth dose (day 4). Data are presented as average % γH2AX positive tissue per total tumor area counted ± standard deviation (N = 4 independent mouse/tumors per point).

Compound 2 has highly attractive physicochemical properties with a low biopharmaceutical risk profile (Table 10). For completeness we examined the methylmorpholine stereoisomers of compounds 2 and 33 and prepared the 3(S)-methylmorpholine matched pairs (compounds 37 and 38 respectively, Table T2 Supporting Information), and these were found to have significantly reduced potency as would be predicted from the described SAR. A stable crystalline form of 2 possesses high solubility in aqueous and biorelevant media such as simulated gastric fluid (SGF) and fasted state simulated intestinal fluid (FaSSIF) (Table 10). Pharmacokinetic evaluation of 2 shows this compound has low to moderate clearance, moderate volume of distribution, and good bioavailability in rodent and dog. Physiologically based pharmacokinetic (PBPK) modeling, (54,55) using in vitro and in vivo data across preclinical species, predicts 2 to have low human clearance (average clearance of 1.98 mL min–1 kg–1) and an estimated volume of distribution of 1 L/kg leading to a terminal half-life of 6 h in man. In silico modeling of human absorption (56) predicts compound 2 will have high bioavailability (∼80%) and a maximum absorbable dose Dabs(25,57) of ∼2500 mg. The preclinical TGI data for compound 2 and related compounds suggest that the duration of free drug exposure is correlated with monotherapy efficacy. A PK/PD model was created linking the preclinical pharmacokinetics of 2 with the DNA-damage biomarker γH2AX and tumor growth inhibition in the LoVo xenograft model. Simulations using the monotherapy LoVo GI50 as the target unbound trough concentration led to a predicted efficacious dose in human (58) of 200 mg (unbound Cmax = 0.93 μM) dosed BD assuming continuous exposure is required across the full dose interval. While it is likely that target drug concentration and/or duration will be lower when ATR inhibitors are dosed in combination, dose prediction based on monotherapy pharmacodynamic modulation and efficacy provides a reasonable basis to estimate the efficacious dose in man. The monotherapy human dose estimate is well below the calculated Dabs, and therefore 2 has low risk of requiring development of an enabling formulation for use in the clinic, whether used alone or in combination. The profound antitumor activity and associated pharmacodynamics combined with favorable dose estimate and pharmaceutical properties led to the sulfoximine 2 being selected for IND-enabling studies, and subsequently this compound became AZD6738.
Table 10. Physicochemical Properties, Preclinical PK, and Predicted Human PK and Dose of 2
 2
estimated pKa3.8 (B1)
 2.2 (B2)
solubility SGF pH 2.5, FaSSIF pH 6.5 (mg/mL)26.7, 0.49
rat PK:a Cl, %LBF/Vdss, L/kg/bioavailability, %22/3.1/67
dog PK:b Cl, %LBF/Vdss, L/kg/bioavailability, %10/1/100
hu CLintc2.0
predicted hu PK: Cl, %LBF/Vdss, L/kg/bioavailability, %/T1/2, h11/1.0/80/6
maximum absorbable dose (Dabs) (mg)d2492
predicted hu dose (mg)e200
a

Rat plasma PK in male Han Wistar rats, dosed at 8.55 (iv) and 20.3 (po) μmol/kg.

b

Dog blood PK in male and female Beagle dogs, dosed at 10.5 (iv) and 15.1 (po) μmol/kg.

c

Estimate of median intrinsic clearance obtained from hepatocyte data using intercept method (59) (μL/min per 1 × 106 cells, 1 μM compound 2).

d

Maximum absorbable dose (Dabs). (25)

e

Predicted human dose assuming unbound trough concentration = 0.43 μM dosed BD.

Compound 2 (AZD6738) has progressed into human clinical trials and is being assessed in multiple phase I/II studies as a monotherapy and in combination with carboplatin (NCT02264678), paclitaxel (NCT02630199), radiotherapy (NCT02223923), and the novel agents olaparib (NCT03462342, NCT03330847), acalabrutinib (NCT03328273), and durvalumab (NCT03334617). Plasma pharmacokinetics in man showed rapid absorption of compound 2, with peak plasma concentration at ∼1.5 h postdose, and a biphasic decline with an elimination half-life of 11.0 h; and despite ∼45% variability in clearance, there was dose proportionality to at least 320 mg QD. (60,61) Plasma pharmacokinetics aligned well with target preclinical free drug exposure and duration, with cover over ATR cell IC90 obtained in ≥50% of patients with a 80–320 mg daily dose range (QD). The observed levels are expected to drive significant ATR inhibition, with cover increasing in a dose dependent manner up to ATR IC96. (62) Preclinical work has demonstrated further potential for combination therapy with, for example, olaparib. (63) Early data from dose escalation studies with combination partners olaparib and durvalumab were presented recently (61) showing good tolerance for compound 2 in combination dose escalation and preliminary signals of antitumor activity, with no evidence of drug–drug interactions (DDI); in 44 patients treated at various doses of compound 2 (60–240 mg QD) in combination with olaparib, 1 RECIST complete response (CR) and 6 partial responses (PR; 1 unconfirmed) were observed in patients with BRCA1 or BRCA2 mutations independent of ATM status, in advanced breast (3 patients), and 1 each of ovarian, prostate, pancreatic, and ampullary cancer; and in 25 patients treated at various doses (80 mg through 240 mg BD) in combination with durvalumab, 1 RECIST CR and 3 PRs, in patients with advanced NSCLC (3 patients) and HNSCC (1 patient), independent of tumor PD-L1 expression were observed. (61)

Conclusions

ARTICLE SECTIONS
Jump To

ATR plays a key role in DNA-damage repair, and only recently highly potent and selective compounds have entered clinical assessment. Here we report the discovery of 2 (AZD6738), an inhibitor of ATR currently being examined in phase I/II clinical trials. Starting from a lead compound containing a sulfone group and substitution with a sulfoximine moiety led to 2, a compound with excellent solubility, good cell potency, and high selectivity across the kinome.
The promising preclinical data package for compound 2 combined with moderate predicted human dose strongly supported its selection as a clinical candidate. First dose of compound 2 in patients was achieved in 2013. Pharmacokinetics in man was found to be dose-dependent with efficacious exposure in alignment with the preclinical prediction together with promising early signs of clinical efficacy. (8,61) AZD6738 is currently in multiple phase II studies as a monotherapy and in combination with carboplatin (NCT02264678), paclitaxel (NCT02630199), radiotherapy (NCT02223923), and the novel agents olaparib (NCT03462342, NCT03330847), acalabrutinib (NCT03328273), and durvalumab (NCT03334617).

Experimental Section

ARTICLE SECTIONS
Jump To

General Synthetic Methods

All experiments were carried out under an inert atmosphere and at room temperature (rt) unless otherwise stated. Microwave reactions were performed using either the Biotage initiator or CEM Explorer. Workup procedures were carried out using traditional phase separating techniques or by using strong cation exchange (SCX) chromatography using Isolute SPE flash SCX-2 column (International Sorbent Technology Limited, Mid Glamorgan, U.K.). When necessary, organic solutions were dried over anhydrous MgSO4 or Na2SO4. Flash column chromatography (FCC) was performed on Merck Kieselgel silica (article 9385) or on Silicycle cartridges (40–63 μm silica, 4–330 g weight) or on GraceResolv cartridges (4–120 g) either manually or automated using an Isco Combi Flash Companion system. Preparative reverse phase HPLC (RP HPLC) was performed on C18 reversed-phase silica, for example, on a Waters “Xterra” or “XBridge” preparative reversed-phase column (5 μm silica, 19 mm diameter, 100 mm length) or on a Phenomenex “Gemini” or “AXIA” preparative reversed-phase column (5 μm silica, 110A, 21.1 mm diameter, 100 mm length) using decreasingly polar mixtures as eluent, for example, containing 0.1% formic acid or 1% aqueous ammonium hydroxide (d = 0.88) as solvent A and acetonitrile as solvent B. The following preperative chiral HPLC methods were used; in general a flow rate of between 10 and 350 mL/min and detection was by UV absorbance at a typical wavelength of 254 nm. A sample concentration of about 1–100 mg/mL was used in a suitable solvent mixture such as MeOH, EtOH, or iPA optionally mixed with isohexane or heptane with an injection volume of between 0.5 and 100 mL and run time of between 10 and 150 min and a typical oven temperature of 25–35 °C. The following analytical chiral HPLC methods were used; in general a flow rate of 1 mL/min and detection was by UV absorbance at a typical wavelength of 254 nm. A sample concentration of about 1 mg/mL was used in a suitable solvent such as EtOH with an injection volume of about 10 μL and run time of between 10 and 60 min and typical oven temperature of 25–35 °C. The following preperative SFC (supercritical fluid chromotography) methods were used; in general a flow rate of about 70 mL/min and detection was by UV absorbance at a typical wavelength of 254 nm. A sample concentration of about 100 mg/mL was used in a suitable solvent such as MeOH with an injection volume of about 0.5 mL and run time of between 10 and 150 min and typical oven temperature of 25–35 °C. Intermediates were not necessarily fully purified, but their structures and purity were assessed by TLC, NMR, HPLC, and mass spectral techniques and are consistent with the proposed structures. The purities of compounds for biological testing were assessed by NMR, HPLC, and mass spectral techniques and are consistent with the proposed structures; purity was ≥95%. Electrospray mass spectral data were obtained using a Waters ZMD or Waters ZQ LC/mass spectrometer acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported. Unless otherwise stated, 1H NMR spectra were obtained using a Bruker DRX400 operating at 400 MHz in DMSO-d6 or CDCl3. Chemical shifts are reported as δ values (ppm) downfield from internal TMS in appropriate organic solutions. Peak multiplicities are expressed as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; br s, broad singlet; m, multiplet. Analytical HPLC was performed on C18 reverse-phase silica, on a Phenomenex “Gemini” preparative reversed-phase column (5 μm silica, 110A, 2 mm diameter, 50 mm length) using decreasingly polar mixtures as eluent, for example, decreasingly polar mixtures of water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B or MeOH/MeCN, 3:1, with a flow rate of about 1 mL/min, and detection was by electrospray mass spectrometry and by UV absorbance at a wavelength of 254 nm. Accurate mass spectra were recorded on a Themo LTQ-FT in +ve ion mode with a Thermo Accela pump and Surveyor PDA+ with a CTC autosampler, and the results agreed with the theoretical values to within 4 ppm. Combustion analyses (C, H, N) were performed with a Carlo Erba EA1108 analyzer, and the results agreed with the theoretical values to within ±0.5%. Water was measured by the Karl Fischer method using a Mettler DL 18. Where the synthesis of an intermediate or reagent is not described it has either been described in the literature previously or is available from commercial sources.

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (2)

Bis(triphenylphosphine)palladium(II) chloride (27.5 g, 39.14 mmol) was added to a suspension of R-75 (259 g, 782.87 mmol), 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (152 g, 939.45 mmol), and sodium carbonate (2 M aq.) (1174 mL, 2348.61 mmol) in degassed DME/H2O (4:1) (2740 mL), and the mixture was stirred to 90 °C for 60 min. A further portion of 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (15.2 g, 93.95 mmol) was added and the reaction stirred for another 60 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL). The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. The crude product was purified by flash chromatography on silica, eluting with a gradient of 0–10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford a cream foam. MTBE (2500 mL) was added and the mixture stirred at room temperature for 3 days before the solid was isolated by filtration to afford 2 (139 g, 42%) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6): 1.19 (3H, d), 1.29–1.50 (3H, m), 1.61–1.72 (1H, m), 3.01 (3H, s), 3.22 (1H, d), 3.43 (1H, td), 3.58 (1H, dd), 3.68–3.76 (2H, m), 3.87–3.96 (1H, m), 4.17 (1H, d), 4.60 (1H, s), 6.98 (1H, s), 7.20 (1H, dd), 7.55–7.58 (1H, m), 7.92 (1H, d), 8.60 (1H, d), 11.67 (1H, s). 13C NMR (176 MHz, DMSO-d6) 11.29, 12.22, 13.39, 38.92, 41.14, 46.48, 47.81, 65.97, 70.19, 101.54, 102.82, 114.58, 117.71, 127.21, 136.70, 142.21, 150.12, 161.88, 162.63, 163.20. HRMS-ESI m/z 413.17529 [MH+]; C20H24N6O2S requires 413.1760. Chiral HPLC: (HP1100 system 4, 5 μm Chiralpak AS-H (250 mm × 4.6 mm) column, eluting with isohexane/EtOH/MeOH/TEA 50/25/25/0.1) Rf = 8.252, >99%. Anal. Found (% w/w): C, 58.36; H, 5.87; N, 20.20; S, 7.55; H2O, <0.14. C20H24N6O2S requires C, 58.23; H, 5.86; N, 20.37; S, 7.77.

4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (2) and 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-((S)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (33)

Dichlorobis(triphenylphosphine)palladium(II) (0.073 g, 0.10 mmol) was added in one portion to R/S-75 (1.383 g, 4.18 mmol), 2 M sodium carbonate (aq) (2.508 mL, 5.02 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3b]pyridine (1.665 g, 4.18 mmol) in DME/water 4:1 (100 mL) under nitrogen. The reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was concentrated and diluted with EtOAc (400 mL) and washed sequentially with water (300 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered, and evaporated onto silica gel (30 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0–5% MeOH in DCM. Pure fractions were evaporated to dryness to afford (3R)-3-methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidin-4-yl)morpholine (2.174 g, 92%). 1H NMR (400 MHz, CDC13): 1.37 (3H, d), 1.56 (2H, m), 1.83 (2H, q), 2.37 (4H, s), 3.16 (3H, s), 3.36 (1H, td), 3.60 (1H, td), 3.74 (1H, dd), 3.85 (1H, d), 4.01–4.19 (2H, m), 4.49 (1H, s), 6.95 (1H, d), 7.28 (2H, d, obscured by CDCl3 peak), 7.44 (1H, t), 7.82 (1H, d), 8.02–8.11 (3H, m), 8.52 (1H, d). MS-ESI m/z 567 [MH+].
(3R)-3-Methyl-4-(6-(1-(S-methylsulfonimidoyl)cyclopropyl)-2-(1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-yl)pyrimidin-4-yl)morpholine (1.67 g, 2.95 mmol) was dissolved in DME/water 4:1 (60 mL) and heated to 50 °C. 2 M Sodium hydroxide (aq.) (2.58 mL, 5.16 mmol) was then added, and heating continued for 18 h. The reaction mixture was acidified with 2 M HCI (∼2 mL) to pH 5. The reaction mixture was evaporated to dryness and the residue dissolved in EtOAc (250 mL) and washed with water (200 mL). The organic layer was dried over MgSO4, filtered, and evaporated onto silica gel (10 g). The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 0–7% MeOH in DCM. Pure fractions were evaporated and the residue was purified by preparative chiral chromatography on a Merck 50 mm, 20 μm ChiralCel OJ column, eluting isocratically with isohexane/EtOH/MeOH/TEA (50/25/25/0.1) as eluent. The fractions containing the desired compound were evaporated to dryness to afford 2 (0.538 g, 44%) as the first eluting compound. 1H NMR (400 MHz, DMSO-d6): 1.29 (3H, d), 1.51 (3H, m), 1.70–1.82 (1H, m), 3.11 (3H, s), 3.28 (1H, m, obscured by water peak), 3.48–3.60 (1H, m), 3.68 (1H, dd), 3.75–3.87 (2H, m), 4.02 (1H, dd), 4.19 (1H, d), 4.60 (1H, s), 7.01 (1H, s), 7.23 (1H, dd), 7.51–7.67 (1H, m), 7.95 (1H, d), 8.34 (1H, d), 11.76 (1H, s). MS-ESI m/z 413 [MH+]. Chiral HPLC: (HP1100 system 4, 5 μm Chiralcel OJ-H (250 mm × 4.6 mm) column eluting with isohexane/EtOH/MeOH/TEA (50/25/25/0.1) Rf = 9.013, >99%; and 33 (0.441 g, 36%) as the second eluting compound. 1H NMR (400 MHz, DMSO-d6) 1.28 (3H, d), 1.40–1.58 (3H, m), 1.70–1.80 (1H, m), 3.10 (3H, d), 3.23–3.27 (1H, m), 3.51 (1H, dt), 3.66 (1H, dd), 3.80 (2H, d), 4.01 (1H, dd), 4.21 (1H, d), 4.56 (1H, s), 6.99 (1H, s), 7.22 (1H, dd), 7.54–7.61 (1H, m), 7.94 (1H, d), 8.33 (1H, d), 11.75 (1H, s). MS-ESI m/z 413 [MH+]. Chiral HPLC: (HP1100 system 4, 5 μm Chiralcel OJ-H (250 mm × 4.6 mm) column eluting with isohexane/EtOH/MeOH/TEA (50/25/25/0.1) Rf = 15.685, >99%.

(R)-4-(2-Chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (71)

Compound 70 (see ref (16)) (17.0 g, 48.1 mmol) was dissolved in DMF (150 mL). To this was added sodium methanethiolate (3.4 g, 48.1 mmol), and the reaction was stirred for 1 h at 25 °C. The reaction mixture was quenched with water (50 mL) and then extracted with Et2O (3 × 50 mL). The combined organic layers were dried over MgSO4, filtered, and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 50–100% EtOAc in isohexane. Pure fractions were evaporated to afford 71 (12.63 g, 96%). 1H NMR (400 MHz, DMSO-d6): 1.20 (3H, d), 2.07 (3H, s), 3.11–3.26 (1H, m), 3.44 (1H, td), 3.53 (2H, s), 3.59 (1H, dd), 3.71 (1H, d), 3.92 (1H, dd), 3.98 (1H, br s), 4.33 (1H, s), 6.77 (1H, s). MS-ESI m/z 274 [MH+].

(3R)-4-(2-Chloro-6-[(methylsulfinyl)methyl]-4-pyrimidinyl)-3-methylmorpholine (R/S-72)

Sodium meta-periodate (2.87 g, 13.44 mmol) was added in one portion to 71 (3.68 g, 13.44 mmol) in water (10 mL), EtOAc (20 mL), and MeOH (10 mL). The resulting solution was stirred at 20 °C for 16 h. The reaction mixture was diluted with DCM (60 mL) and then filtered. The DCM layer was separated and the aqueous layer washed with DCM (3 × 40 mL). The organic layers were combined, dried over MgSO4, filtered, and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0–7% MeOH in DCM. Pure fractions were evaporated to afford R/S-72 (2.72 g, 70%). 1H NMR (400 MHz, DMSO-d6): 1.22 (3H, d), 2.64 (3H, d), 3.14–3.26 (1H, m), 3.45 (1H, td), 3.59 (1H, dd), 3.73 (1H, d), 3.88–3.96 (2H, m), 4.00 (1H, d), 4.07 (1H, dt), 4.33 (1H, s), 6.81 (1H, s). MS-ESI m/z 290 [MH+].

(R)-4-(2-Chloro-6-((S)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (S-72) and (R)-4-(2-chloro-6-((R)-methylsulfinylmethyl)pyrimidin-4-yl)-3-methylmorpholine (R-72)

Compound R/S-72 (2.7 g, 9.32 mmol) was purified by preparative chiral chromatography on a Merck 100 mm 20 μm Chiralpak AD column, eluting isocratically with a 50:50:0.1 mixture of isohexane/EtOH/TEA as eluent. The fractions containing product were evaporated to afford S-72 (1.38 g, 51%) as the first eluting compound. 1H NMR (CDCl3): 1.29 (3H, dd), 2.56 (3H, s), 3.15–3.33 (1H, m), 3.46 (1H, tt), 3.55–3.83 (3H, m), 3.85–4.06 (3H, m), 4.31 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 system 6, 20 μm Chiralpak AD (250 mm × 4.6 mm) column eluting with isohexane/EtOH/TEA 50/50/0.1) Rf = 7.197, >99% and R-72 (1.27 g, 47%) as the second eluting compound. 1H NMR (400 MHz, CDCl3): 1.28 (3H, d), 2.58 (3H, s), 3.26 (1H, td), 3.48 (1H, td), 3.62 (1H, dt), 3.77 (2H, dd), 3.88–4.13 (3H, m), 4.28 (1H, s), 6.37 (1H, s). Chiral HPLC: (HP1100 System 6, 20 μm Chiralpak AD (250 mm × 4.6 mm) column eluting with isohexane/EtOH/TEA 50/50/0.1) Rf = 16.897, >99%.
Compound R-72 was prepared on a large scale as follows:
Sodium meta-periodate (960 g, 4488.24 mmol) was added portionwise to 71 (1024 g, 3740.20 mmol) in water (3000 mL), EtOAc (6000 mL), and MeOH (3000 mL). The resulting solution was stirred at 17 °C for 16 h. The reaction was diluted with DCM (18000 mL) and water (3000 mL). The DCM layer was separated and the water layer washed with DCM (3 × 5000 mL). The organics were combined and dried over MgSO4 and sodium bisulphite, filtered, and evaporated. The crude product was purified by flash chromatography on silica, eluting with a gradient of 10–50% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford R/S-72 (935 g, 86%).
Compound R/S-72 (1933 g, 6670.58 mmol) was purified by preparative chiral chromatography on a Merck 100 mm 20 μm Chiralpak AD column, eluting isocratically with a 50:50:0.1 mixture of isohexane/EtOH/TEA as eluent. The fractions containing product were evaporated to afford R-72 (886.4 g, 46%) as the second eluting compound. 1H NMR (400 MHz, CDCl3, 30 °C): 1.28 (3H, d), 2.58 (3H, s), 3.26 (1H, td), 3.48 (1H, td), 3.62 (1H, dt), 3.77 (2H, dd), 3.88–4.13 (3H, m), 4.28 (1H, s), 6.37 (1H, s). MS-ESI m/z 290, 292 [MH+]. Chiral HPLC: (20 μm Chiralpak AD (250 mm × 4.6 mm) column eluting with isohexane/EtOH/TEA 50/50/0.1) Rf = 16.897, >99%.

N-[({2-Chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (R/S-74)

Iodobenzene diacetate (6.54 g, 20.29 mmol) was added to R/S-72 (5.88 g, 20.29 mmol), 2,2,2-trifluoroacetamide (4.59 g, 40.58 mmol), magnesium oxide (3.27 g, 81.16 mmol), and rhodium(II) acetate dimer (0.224 g, 0.51 mmol) in DCM (169 mL) under air. The resulting suspension was stirred at room temperature for 3 days. Further 2,2,2-trifluoroacetamide (1.15 g, 10.15 mmol), magnesium oxide (0.818 g, 20.29 mmol), rhodium(II) acetate dimer (0.056 g, 0.13 mmol), and iodobenzene diacetate (l 0.64 g, 5.07 mmol) were added, and the suspension was stirred at room temperature for a further 24 h. The reaction mixture was filtered. Silica gel (3 g) was added to the filtrate, and then the mixture was evaporated. The resulting powder was purified by flash chromatography on silica, eluting with a gradient of 20–50% EtOAc in isohexane. Fractions containing product were evaporated and the residue was triturated with isohexane/MTBE to give a solid which was collected by filtration and dried under vacuum to afford R/S-74 (6.64 g, 82%). 1H NMR (400 MHz, CDC13): 1.33 (3H, d), 3.28 (1H, dd), 3.43 (3H, d), 3.46–3.59 (1H, m), 3.62–3.71 (1H, m), 3.79 (1H, d), 3.90–4.50 (2H, br s), 4.21 (1H, s), 4.66 (1H, dd), 4.86 (1H, dd), 6.50 (1H, d). MS-ESI m/z 401, 403 [MH+].

N-[({2-Chloro-6-[(3R)-3-methylmorpholin-4-yl]pyrimidin-4-yl}methyl)(R-methyl)oxido-λ6-sulfanylidene]-2,2,2-trifluoroacetamide (R-74)

To a stirring solution of R-72 (285 g, 983.50 mmol) in DCM (2810 mL) were added magnesium oxide (159 g, 3934.00 mmol), iodobenzene diacetate (475 g, 1475.25 mmol), rhodium(II) acetate dimer (10.87 g, 24.59 mmol), and 2,2,2-trifluoroacetamide (222 g, 1967.00 mmol). The mixture was maintained at room temperature under air for 16 h. The resultant light brown suspension was removed by filtration. The filtrate was evaporated then purified by flash chromatography on silica, eluting with a gradient of 30–100% EtOAc in heptane. Pure fractions were evaporated to afford R-74 (306 g, 77%). 1H NMR (400 MHz, CDCl3, 30 °C): 1.33 (3H, d), 3.25–3.38 (1H, m), 3.42 (3H, s), 3.51 (1H, td), 3.66 (1H, dd), 3.79 (1H, d), 4.01 (1H, dd), 4.31 (1H, s), 4.64 (1H, d), 4.77–4.87 (1H, m), 6.48 (1H, d). MS-ESI m/z 401, 403 [MH+].

(3R)-4-(2-Chloro-6-(1-(S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (R/S-75)

Sodium hydroxide (50% aq) (217 mL, 4059.84 mmol) was added to R/S-74 (27.12 g, 67.66 mmol), 1,2-dibromoethane (23.3 mL, 270.66 mmol), and tetraoctylammonium bromide (3.70 g, 6.77 mmol) in methyl THF (1000 mL) at 20 °C under nitrogen. The resulting mixture was stirred at 20 °C for 24 h. Further 1,2-dibromoethane (23.3 mL, 270.66 mmol) was added, and the mixture was stirred at 20 °C for a further 24 h. The reaction mixture was diluted with mTHF (1000 mL) and the aqueous layer separated. The organic layer was diluted further with EtOAc (1000 mL) and washed with water (1500 mL). The organic layer was dried over MgSO4, filtered, and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 0–5% MeOH in DCM. Pure fractions were evaporated to afford R/S-75 (14.80 g, 66%). 1H NMR (400 MHz, DMSO-d6): 1.21 (3H, d), 1.39 (3H, m), 1.62–1.71 (1H, m), 3.01 (3H, s), 3.43 (1H, tt), 3.58 (1H, dd), 3.72 (1H, d), 3.82 (1H, d), 3.93 (1H, dd), 4.01 (1H, s), 4.38 (1H, s), 6.96 (1H, d). MS-ESI m/z 331, 333 [MH+].

(3R)-4-(2-Chloro-6-(1-((R)-S-methylsulfonimidoyl)cyclopropyl)pyrimidin-4-yl)-3-methylmorpholine (R-75)

To a solution of R-74 (476 g, 1188 mmol), 1,2-dibromoethane (1023 mL, 11876 mmol), and tetraoctylammonium bromide (64.9 g, 118.76 mmol) in mTHF (4750 mL) was added sodium hydroxide (3170 mL, 59380.59 mmol) over 10 min. The mixture was stirred for 4 h at room temperature. The organic layer was separated, washed with brine (2000 mL), dried over MgSO4, and then filtered. The filtrate was evaporated and then purified by flash chromatography on silica, eluting with a gradient of 0–5% MeOH in EtOAc. Pure fractions were evaporated to afford R-75 (259 g, 66%). 1H NMR (400 MHz, DMSO-d6): 1.14–1.21 (m, 4 H) 1.22–1.32 (m, 7 H) 1.34–1.47 (m, 3 H) 1.56 (br. s., 1 H) 1.59–1.71 (m, 1 H) 3.00 (d, J = 1.27 Hz, 3 H) 3.09–3.23 (m, 2 H) 3.29 (s, 2 H) 3.42 (td, J = 11.85, 2.91 Hz, 1 H) 3.57 (dd, J = 11.53, 3.17 Hz, 1 H) 3.70 (d, J = 11.41 Hz, 1 H) 3.81 (s, 1 H) 3.92 (dd, J = 11.53, 3.68 Hz, 1 H) 3.95–4.13 (m, 1 H) 4.37 (br s, 1 H) 6.95 (s, 1 H). MS-ESI m/z 331, 333 [MH+].

Biological Evaluation

IC50 values reported are geometric mean values of at least two independent measurements unless otherwise stated.

Cell Line Studies

Cells lines were grown in RPMI-1640 media, 10% FCS, 2 mmol/L glutamine at 37 °C/5% CO2 unless indicated otherwise. All cell lines were authenticated via the AstraZeneca (AZ) Cell Bank using DNA fingerprinting short tandem repeat (STR) assays. All revived cells were used within 20 passages and cultured for less than 6 months.

ATR Kinase Assay

This assay is described in Foote et al. (16)

ATR Cell (pChk1) Assay in HT29 Tumor Cells

This assay is a variation on that described in Foote et al., (16) with the use of alternative primary pCHK1 S345 antibodies (Cell Signaling Technologies) and secondary AlexaFluor-488 antibody (Molecular Probes).

In Vivo Studies

All animal experiments were conducted in full accordance with the U.K. Home Office Animal (Scientific Procedures) Act 1986. Antitumor studies: Female Swiss nu/nu mice (AstraZeneca, U.K.) were housed in negative pressure isolators (PFI Systems Ltd., Oxon, U.K.). LoVo tumor xenografts were established in 8- to 12-week-old mice by injecting 1 × 107 tumor cells subcutaneously (100 μL in serum free medium) on the left dorsal flank. Animals were randomized into treatment groups when tumors became palpable. Compound 2 was administered orally. Tumors were measured up to three times per week with calipers. Tumor volumes were calculated and the data plotted using the geometric mean for each group versus time.

γH2AX Immunohistochemistry Pharmacodynamic Analysis (PD)

Four tumors were used per point. Sections of tissue 4 μm were cut on a microtome (Thermo Fisher Scientific) and mounted on electrostatically charged glass slides (Thermo Fisher Scientific). Sections were dewaxed in xylene, passed through graded alcohols, and rehydrated in water. Heat mediated antigen retrieval was performed using a RHS2 microwave (Milestone) at 110 °C for 2 min in pH 9.0 Target Retrieval Solution (catalog no. S2367, Dako UK Ltd.). Immunohistochemistry was then performed at room temperature on a Lab Vision Autostainer 480 (Lab Vision). 0.05 M Tris buffered saline with 0.1% Tween 20 (TBST), pH 7.6, was used for both the reagent and wash buffers. Sections were treated with 10% hydrogen peroxide in TBST for 10 min, washed, and incubated with Background Blocker (catalog no. MP-966-P500, A.Menarini Diagnostics Ltd.) for 20 min. Sections were incubated with antiphospho-Ser139 (γ)H2AX (catalog no. 2577, Cell Signaling Technology) for 1 h before washing and incubating with X-Cell Polymer HRP for 15 min before being visualized by incubation with the chromogen, diaminobenzidine (DAB) (catalog no. MP-, A.Menarini Diagnostics Ltd.), for 10 min. Sections were washed for 10 min in H2O and counterstained with Carrazzis hematoxylin (Clin-Tech), dehydrated though graded IMS, cleared in xylene, and mounted using glass coverslips and Histomount (RA Lamb). Slides were scanned and digitized using an Scanscope XT slide scanner (Aperio) at ×20 magnification. Once scanned, all digital images representing whole tissue sections were evaluated for image quality. Immunohistochemistry staining was then quantified using the Spectrum Analysis algorithm package and Image Scope viewing software (Aperio). Data are presented as % γH2AX positive tissue from total tissue area counted, through quantification of pixel counts for γH2AX positive c (brown) and hematoxylin only tissue (blue) staining. Only viable tumor was included in the analysis (necrotic areas were excluded). Four independent mouse tumors were analyzed per time point.

Supporting Information

ARTICLE SECTIONS
Jump To

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01187.

  • Figure S1 showing kinome tree graphs for 3, 21, 15; Table T1 listing kinase inhibition data for 2; Table T2 listing ATR activity data for 37, 38; Scheme S1 showing synthetic route to 37 and 38; crystallization methods for compound 2; experimental details and data for compounds 532, 3438, 4045, 5069, R/S-73, 7779; crystal formation method of R-72; Figure S2 showing X-ray structure of R-72; aqueous solubility, log D7.4 methods (PDF)

  • Molecular formula strings (CSV)

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

ARTICLE SECTIONS
Jump To

  • Corresponding Author
  • Authors
    • Kevin M. Foote - Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.Present Address: K.M.F.: Pharmaron, Drug Discovery Services Europe, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU, U.K
    • Thomas McGuire - Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
    • Paul Turner - Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
    • Sylvie Guichard - Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.Present Address: S.G.: Forma Therapeutics, 500 Arsenal Street, Watertown, MA 02472, U.S
    • James W. T. Yates - DMPK, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
    • Alan Lau - Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
    • Kevin Blades - Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.Present Address: K.B.: AMR Centre Ltd., 19B70, Mereside Alderley Park, Alderley Edge, SK10 4T, U.K
    • Dan Heathcote - Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
    • Rajesh Odedra - Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.Present Address: R.O.: Evotec, 114 Innovation Drive, Milton Park, Abingdon Oxfordshire OX14 4RZ, U.K
    • Gary Wilkinson - Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.Present Address: G.W.: Bayer, Müllerstraße 178, 13353, Berlin, Germany
    • Zena Wilson - Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Chesterford Research Park, Little Chesterford, Cambridge CB10 1XL, U.K.
    • Christine M. Wood - Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
    • Philip J. Jewsbury - Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge Science Park, 310 Milton Road, Milton, Cambridge CB4 0WG, U.K.
  • Notes
    The authors declare the following competing financial interest(s): All authors were employees of AstraZeneca at the time of research and may hold or have held AstraZeneca stock or stock options.

Acknowledgments

ARTICLE SECTIONS
Jump To

We acknowledge Lorraine Hassall, Craig Robertson, Jessica Boyd, and Adrian Pickup for their contribution to chemical synthesis; Rebecca Broadhurst, Daren Cumberbatch, Darren Jones, Graeme Scarfe, and Kin Tam for DMPK and physicochemical property characterization; Lisa Smith, Victoria Pearson, Alex Crooks, Jon Tart, Natalie Stratton, Catherine Bardelle, Lindsey Leach, Linda MacCallum, and David Nicholls for biochemical and cell assays; Adina Hughes, Elaine Brown, Roz Brant, and Steve Powell for biological cell and in vivo pharmacodynamic assays; Anna Cronin, Katie Stamp, and Jennifer Barnes for safety, toxicology, and pathology assessments; Paul Davey for mass spectrometry and Caroline MacMillan for purification; David Berry, Anne Ertan for small-molecule crystal generation and structure processing; Kristin Goldberg for help with preparing the manuscript. Finally, we highlight the close collaboration with scientists at KuDOS in the early stages of the project and past and present members of the ATR project team, specifically Aaron Cranston, Ian Hickson, Xavier Jacq, Cliff Jones, and Pia Thommes.

Abbreviations Used

ARTICLE SECTIONS
Jump To

ACN

acetonitrile

API

active pharmaceutical ingredient

ATM

ataxia telangiectasia mutated

ATR

ataxia telangiectasia mutated and rad3 related

AUC

area under the curve

BD

bis in die, twice daily

CLint

intrinsic clearance

CYP3A4

cyptochrome P450 3A4 isoform

Dabs

maximum absorbable dose

DCM

dichloromethane

DDI

drug–drug interaction

DDR

DNA-damage response

DIPEA

diisopropylethylamine

DMA

N,N-dimethylacetamide

DMAP

4-dimethylaminopyridine

DME

1,2-dimethoxyethane

DMF

N,N-dimethylformamide

DMSO

dimethylsulfoxide

DNA-PK

DNA-dependent protein kinase

DSB

double strand break

Et2O

diethyl ether

EtOAc

ethyl acetate

EtOH

ethanol

γ-H2AX

variant histone

H2A

phosphorylated

GSH

glutathione

hERG

human ether-a-go-go-related gene

IND

Investigational New Drug

IPA

2-propanol

LCMS

liquid chromatography–mass spectrometry

IR

ionizing radiation

MeOH

methanol

mTHF

2-methyltetrahydrofuran

MTBE

methyl tert-butyl ether

mTOR

mammalian target of rapamycin

PBPK

physiologically based pharmacokinetics

PK

pharmacokinetics

PIKK

phosphatidylinositol 3-kinase-related kinase

PI3K

phosphatidylinositol 3-kinase

RSR

replication stress response

SAR

structure–activity relationship

SOC

standard of care

TDI

time-dependent inhibitor

TFA

trifluoroacetic acid

THF

tetrahydrofuran

TGI

tumor growth inhibition

Vdss

volume of distribution at steady state

QD

quaque die, once daily.

References

ARTICLE SECTIONS
Jump To

This article references 63 other publications.

  1. 1
    O’Connor, M. J. Targeting the DNA damage response in cancer. Mol. Cell 2015, 60, 547560,  DOI: 10.1016/j.molcel.2015.10.040
  2. 2
    Jackson, S. P.; Helleday, T. DNA Repair. Drugging DNA repair. Science 2016, 352, 11781179,  DOI: 10.1126/science.aab0958
  3. 3
    Yazinski, S. A.; Zou, L. Functions, regulation, and therapeutic implications of the ATR checkpoint pathway. Annu. Rev. Genet. 2016, 50, 155173,  DOI: 10.1146/annurev-genet-121415-121658
  4. 4
    Cimprich, K. A.; Cortez, D. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 2008, 9, 616627,  DOI: 10.1038/nrm2450
  5. 5
    Macheret, M.; Halazonetis, T. D. DNA replication stress as a hallmark of cancer. Annu. Rev. Pathol.: Mech. Dis. 2015, 10, 425448,  DOI: 10.1146/annurev-pathol-012414-040424
  6. 6
    Foote, K. M.; Lau, A.; Nissink, J. W. M. Drugging ATR: progress in the development of specific inhibitors for the treatment of cancer. Future Med. Chem. 2015, 7, 873891,  DOI: 10.4155/fmc.15.33
  7. 7
    Weber, A. M.; Ryan, A. J. ATM and ATR as therapeutic targets in cancer. Pharmacol. Ther. 2015, 149, 124138,  DOI: 10.1016/j.pharmthera.2014.12.001
  8. 8
    Sundar, R.; Brown, J.; Ingles Russo, A.; Yap, T. A. Targeting ATR in cancer medicine. Curr. Probl. Cancer 2017, 41, 302315,  DOI: 10.1016/j.currproblcancer.2017.05.002
  9. 9
    Rundle, S.; Bradbury, A.; Drew, Y.; Curtin, N. J. Targeting the ATR-CHK1 axis in cancer therapy. Cancers 2017, 9, E41,  DOI: 10.3390/cancers9050041
  10. 10
    Kwok, M.; Davies, N.; Agathanggelou, A.; Smith, E.; Oldreive, C.; Petermann, E.; Stewart, G.; Brown, J.; Lau, A.; Pratt, G.; Parry, H.; Taylor, M.; Moss, P.; Hillmen, P.; Stankovic, T. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood 2016, 127, 582595,  DOI: 10.1182/blood-2015-05-644872
  11. 11
    Min, A.; Im, S. A.; Jang, H.; Kim, S.; Lee, M.; Kim, D. K.; Yang, Y.; Kim, H. J.; Lee, K. H.; Kim, J. W.; Kim, T. Y.; Oh, D. Y.; Brown, J.; Lau, A.; O’Connor, M. J.; Bang, Y. J. AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells. Mol. Cancer Ther. 2017, 16, 566577,  DOI: 10.1158/1535-7163.MCT-16-0378
  12. 12
    Vendetti, F. P.; Lau, A.; Schamus, S.; Conrads, T. P.; O’Connor, M. J.; Bakkenist, C. J. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget 2015, 6, 4428944305,  DOI: 10.18632/oncotarget.6247
  13. 13
    Dillon, M. T.; Barker, H. E.; Pedersen, M.; Hafsi, H.; Bhide, S. A.; Newbold, K. L.; Nutting, C. M.; McLaughlin, M.; Harrington, K. J. Radiosensitization by the ATR inhibitor AZD6738 through generation of acentric micronuclei. Mol. Cancer Ther. 2017, 16, 2534,  DOI: 10.1158/1535-7163.MCT-16-0239
  14. 14
    Dunne, V.; Ghita, M.; Small, D. M.; Coffey, C. B. M.; Weldon, S.; Taggart, C. C.; Osman, S. O.; McGarry, C. K.; Prise, K. M.; Hanna, G. G.; Butterworth, K. T. Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy. Radiother. Oncol. 2017, 124, 475481,  DOI: 10.1016/j.radonc.2017.06.025
  15. 15
    Kim, H.; George, E.; Ragland, R.; Rafail, S.; Zhang, R.; Krepler, C.; Morgan, M.; Herlyn, M.; Brown, E.; Simpkins, F. Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models. Clin. Cancer Res. 2017, 23, 30973108,  DOI: 10.1158/1078-0432.CCR-16-2273
  16. 16
    Foote, K. M.; Blades, K.; Cronin, A.; Fillery, S.; Guichard, S. S.; Hassall, L.; Hickson, I.; Jacq, X.; Jewsbury, P. J.; McGuire, T. M.; Nissink, J. W.; Odedra, R.; Page, K.; Perkins, P.; Suleman, A.; Tam, K.; Thommes, P.; Broadhurst, R.; Wood, C. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-y l}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J. Med. Chem. 2013, 56, 21252138,  DOI: 10.1021/jm301859s
  17. 17
    Menezes, D. L.; Holt, J.; Tang, Y.; Feng, J.; Barsanti, P.; Pan, Y.; Ghoddusi, M.; Zhang, W.; Thomas, G.; Holash, J.; Lees, E.; Taricani, L. A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function. Mol. Cancer Res. 2015, 13, 120129,  DOI: 10.1158/1541-7786.MCR-14-0240
  18. 18
    Wengner, A.; Siemeister, G.; Luecking, U.; Lefranc, J.; Lienau, P.; Deeg, G.; Lagkadinou, E.; Liu, L.; Golfier, S.; Schatz, C.; Scholz, A.; von Nussbaum, F.; Brands, M.; Mumberg, D.; Ziegelbauer, K. ATR Inhibitor BAY 1895344 Shows Potent Anti-Tumor Efficacy in Monotherapy and Strong Combination Potential with the Targeted Alpha Therapy Radium-223 Dichloride in Preclinical Tumor Models. Proceedings, AACR Annual Meeting, Washington, DC, 2017; AACR: Philadelphia, PA, 2017.
  19. 19
    Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-catalyzed cross-coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters. J. Org. Chem. 1995, 60, 75087510,  DOI: 10.1021/jo00128a024
  20. 20
    Goundry, W. R. F.; Adams, B.; Benson, H.; Demeritt, J.; McKown, S.; Mulholland, K.; Robertson, A.; Siedlecki, P.; Tomlin, P.; Vare, K. Development and scale-up of a biocatalytic process to form a chiral sulfoxide. Org. Process Res. Dev. 2017, 21, 107113,  DOI: 10.1021/acs.oprd.6b00391
  21. 21
    Okamura, H.; Bolm, C. Rhodium-catalyzed imination of sulfoxides and sulfides: efficient preparation of N-unsubstituted sulfoximines and sulfilimines. Org. Lett. 2004, 6, 13051307,  DOI: 10.1021/ol049715n
  22. 22
    Dresser, G. K.; Spence, J. D.; Bailey, D. G. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin. Pharmacokinet. 2000, 38, 4157,  DOI: 10.2165/00003088-200038010-00003
  23. 23
    Kalgutkar, A. S.; Obach, R. S.; Maurer, T. S. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Curr. Drug Metab. 2007, 8, 407447,  DOI: 10.2174/138920007780866807
  24. 24
    Hollenberg, P. F.; Kent, U. M.; Bumpus, N. N. Mechanism-based inactivation of human cytochromes p450s: experimental characterization, reactive intermediates, and clinical implications. Chem. Res. Toxicol. 2008, 21, 189205,  DOI: 10.1021/tx7002504
  25. 25
    Curatolo, W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm. Sci. Technol. Today 1998, 1, 387393,  DOI: 10.1016/S1461-5347(98)00097-2
  26. 26
    Kenny, J. R.; Mukadam, S.; Zhang, C.; Tay, S.; Collins, C.; Galetin, A.; Khojasteh, S. C. Drug-drug interaction potential of marketed oncology drugs: in vitro assessment of time-dependent cytochrome P450 inhibition, reactive metabolite formation and drug-drug interaction prediction. Pharm. Res. 2012, 29, 19601976,  DOI: 10.1007/s11095-012-0724-6
  27. 27
    Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 2011, 24, 13451410,  DOI: 10.1021/tx200168d
  28. 28
    Cytochrome P450 3A4 and 3A5 Known Drug Interaction Chart. http://www.mayomedicallaboratories.com/it-mmfiles/Cytochrome_P450_3A4_and_3A5_Known_Drug_Interaction_Chart.pdf (accessed June 5, 2018).
  29. 29
    Overton, M.; Hickman, J. A.; Threadgill, M. D.; Vaughan, K.; Gescher, A. The generation of potentially toxic, reactive iminium ions from the oxidative metabolism of xenobiotic N-alkyl compounds. Biochem. Pharmacol. 1985, 34, 20552061,  DOI: 10.1016/0006-2952(85)90394-6
  30. 30
    Masic, L. P. Role of cyclic tertiary amine bioactivation to reactive iminium species: structure toxicity relationship. Curr. Drug Metab. 2011, 12, 3550,  DOI: 10.2174/138920011794520044
  31. 31
    Bolleddula, J.; DeMent, K.; Driscoll, J. P.; Worboys, P.; Brassil, P. J.; Bourdet, D. L. Biotransformation and bioactivation reactions of alicyclic amines in drug molecules. Drug Metab. Rev. 2014, 46, 379419,  DOI: 10.3109/03602532.2014.924962
  32. 32
    Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell, J. P. Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem. Res. Toxicol. 2002, 15, 269299,  DOI: 10.1021/tx015574b
  33. 33
    Inoue, K.; Fukuda, K.; Yoshimura, T.; Kusano, K. Comparison of the reactivity of trapping reagents toward electrophiles: cysteine derivatives can be bifunctional trapping reagents. Chem. Res. Toxicol. 2015, 28, 15461555,  DOI: 10.1021/acs.chemrestox.5b00129
  34. 34
    Atkinson, A.; Kenny, J. R.; Grime, K. Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis. Drug. Metab. Dispos. 2005, 33, 16371647,  DOI: 10.1124/dmd.105.005579
  35. 35
    Kaplan, J.; Verheijen, J. C.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Yu, K.; Zask, A. Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Bioorg. Med. Chem. Lett. 2010, 20, 640643,  DOI: 10.1016/j.bmcl.2009.11.050
  36. 36
    Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.; Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Yu, K. Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors. J. Med. Chem. 2009, 52, 79427945,  DOI: 10.1021/jm901415x
  37. 37
    Safina, B. S.; Baker, S.; Baumgardner, M.; Blaney, P. M.; Chan, B. K.; Chen, Y. H.; Cartwright, M. W.; Castanedo, G.; Chabot, C.; Cheguillaume, A. J.; Goldsmith, P.; Goldstein, D. M.; Goyal, B.; Hancox, T.; Handa, R. K.; Iyer, P. S.; Kaur, J.; Kondru, R.; Kenny, J. R.; Krintel, S. L.; Li, J.; Lesnick, J.; Lucas, M. C.; Lewis, C.; Mukadam, S.; Murray, J.; Nadin, A. J.; Nonomiya, J.; Padilla, F.; Palmer, W. S.; Pang, J.; Pegg, N.; Price, S.; Reif, K.; Salphati, L.; Savy, P. A.; Seward, E. M.; Shuttleworth, S.; Sohal, S.; Sweeney, Z. K.; Tay, S.; Tivitmahaisoon, P.; Waszkowycz, B.; Wei, B.; Yue, Q.; Zhang, C.; Sutherlin, D. P. Discovery of novel PI3-kinase delta specific inhibitors for the treatment of rheumatoid arthritis: taming CYP3A4 time-dependent inhibition. J. Med. Chem. 2012, 55, 58875900,  DOI: 10.1021/jm3003747
  38. 38
    Pennington, L. D.; Moustakas, D. T. The necessary nitrogen atom: a versatile high-impact design element for multiparameter optimization. J. Med. Chem. 2017, 60, 35523579,  DOI: 10.1021/acs.jmedchem.6b01807
  39. 39
    Lu, Y.; Knapp, M.; Crawford, K.; Warne, R.; Elling, R.; Yan, K.; Doyle, M.; Pardee, G.; Zhang, L.; Ma, S.; Mamo, M.; Ornelas, E.; Pan, Y.; Bussiere, D.; Jansen, J.; Zaror, I.; Lai, A.; Barsanti, P.; Sim, J. Rationally designed PI3Kalpha mutants to mimic ATR and their use to understand binding specificity of ATR inhibitors. J. Mol. Biol. 2017, 429, 16841704,  DOI: 10.1016/j.jmb.2017.04.006
  40. 40
    Rao, Q.; Liu, M.; Tian, Y.; Wu, Z.; Hao, Y.; Song, L.; Qin, Z.; Ding, C.; Wang, H. W.; Wang, J.; Xu, Y. Cryo-EM structure of human ATR-ATRIP complex. Cell Res. 2018, 28, 143156,  DOI: 10.1038/cr.2017.158
  41. 41
    Adler, T. K.; Albert, A. Diazaindenes (“azaindoles”). Part I. Ionization constants and spectra. J. Chem. Soc. 1960, 0, 17941797,  DOI: 10.1039/JR9600001794
  42. 42
    Kawashima, S.; Matsuno, T.; Yaguchi, S.; Sasahara, H.; Watanabe, T. Heterocyclic Compound and Antitumor Agent Containing the Same as Active Ingredient. WO2002088112, 2002.
  43. 43
    Scott, J. S.; Birch, A. M.; Brocklehurst, K. J.; Broo, A.; Brown, H. S.; Butlin, R. J.; Clarke, D. S.; Davidsson, O.; Ertan, A.; Goldberg, K.; Groombridge, S. D.; Hudson, J. A.; Laber, D.; Leach, A. G.; Macfaul, P. A.; McKerrecher, D.; Pickup, A.; Schofield, P.; Svensson, P. H.; Sorme, P.; Teague, J. Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation. J. Med. Chem. 2012, 55, 53615379,  DOI: 10.1021/jm300310c
  44. 44
    Lucking, U. Sulfoximines: a neglected opportunity in medicinal chemistry. Angew. Chem., Int. Ed. 2013, 52, 93999408,  DOI: 10.1002/anie.201302209
  45. 45
    Sirvent, J. A.; Lucking, U. Novel pieces for the emerging picture of sulfoximines in drug discovery: synthesis and evaluation of sulfoximine analogues of marketed drugs and advanced clinical candidates. ChemMedChem 2017, 12, 487501,  DOI: 10.1002/cmdc.201700044
  46. 46
    Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Sulfoximines from a medicinal chemist’s perspective: physicochemical and in vitro parameters relevant for drug discovery. Eur. J. Med. Chem. 2017, 126, 225245,  DOI: 10.1016/j.ejmech.2016.09.091
  47. 47
    Redfern, W. S.; Carlsson, L.; Davis, A. S.; Lynch, W. G.; MacKenzie, I.; Palethorpe, S.; Siegl, P. K.; Strang, I.; Sullivan, A. T.; Wallis, R.; Camm, A. J.; Hammond, T. G. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 2003, 58, 3245,  DOI: 10.1016/S0008-6363(02)00846-5
  48. 48
    Fokas, E.; Prevo, R.; Pollard, J. R.; Reaper, P. M.; Charlton, P. A.; Cornelissen, B.; Vallis, K. A.; Hammond, E. M.; Olcina, M. M.; Gillies McKenna, W.; Muschel, R. J.; Brunner, T. B. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012, 3, e441,  DOI: 10.1038/cddis.2012.181
  49. 49
    Jacq, X.; Smith, L.; Brown, E.; Hughes, A.; Odedra, R.; Heathcote, D.; Barnes, J.; Powell, S.; Maguire, S.; Pearson, V.; Boros, J.; Caie, P.; Thommes, P. A.; Nissink, W.; Foote, K.; Jewsbury, P. J.; Guichard, S. M. AZ20, a novel potent and selective inhibitor of ATR kinase with in vivo antitumour activity. Cancer Res. 2012, 72 (8, Suppl.), 1823,  DOI: 10.1158/1538-7445.AM2012-1823
  50. 50
    Barlaam, B.; Cosulich, S.; Degorce, S.; Fitzek, M.; Green, S.; Hancox, U.; Lambert-van der Brempt, C.; Lohmann, J. J.; Maudet, M.; Morgentin, R.; Pasquet, M. J.; Peru, A.; Ple, P.; Saleh, T.; Vautier, M.; Walker, M.; Ward, L.; Warin, N. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chrom ene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kbeta and PI3Kdelta for the treatment of PTEN-deficient cancers. J. Med. Chem. 2015, 58, 943962,  DOI: 10.1021/jm501629p
  51. 51
    Barlaam, B.; Cosulich, S.; Delouvrie, B.; Ellston, R.; Fitzek, M.; Germain, H.; Green, S.; Hancox, U.; Harris, C. S.; Hudson, K.; Lambert-van der Brempt, C.; Lebraud, H.; Magnien, F.; Lamorlette, M.; Le Griffon, A.; Morgentin, R.; Ouvry, G.; Page, K.; Pasquet, G.; Polanska, U.; Ruston, L.; Saleh, T.; Vautier, M.; Ward, L. Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4 -triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kalpha and PI3Kdelta for the treatment of cancers. Bioorg. Med. Chem. Lett. 2015, 25, 51555162,  DOI: 10.1016/j.bmcl.2015.10.002
  52. 52
    Bonner, W. M.; Redon, C. E.; Dickey, J. S.; Nakamura, A. J.; Sedelnikova, O. A.; Solier, S.; Pommier, Y. GammaH2AX and cancer. Nat. Rev. Cancer 2008, 8, 957967,  DOI: 10.1038/nrc2523
  53. 53
    Chen, T.; Middleton, F. K.; Falcon, S.; Reaper, P. M.; Pollard, J. R.; Curtin, N. J. Development of pharmacodynamic biomarkers for ATR inhibitors. Mol. Oncol. 2015, 9, 463472,  DOI: 10.1016/j.molonc.2014.09.012
  54. 54
    Nestorov, I. A.; Aarons, L. J.; Arundel, P. A.; Rowland, M. Lumping of whole-body physiologically based pharmacokinetic models. J. Pharmacokinet. Biopharm. 1998, 26, 2146
  55. 55
    Luttringer, O.; Theil, F. P.; Poulin, P.; Schmitt-Hoffmann, A. H.; Guentert, T. W.; Lave, T. Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans. J. Pharm. Sci. 2003, 92, 19902007,  DOI: 10.1002/jps.10461
  56. 56
    Sjögren, E.; Westergren, J.; Grant, I.; Hanisch, G.; Lindfors, L.; Lennernas, H.; Abrahamsson, B.; Tannergren, C. In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur. J. Pharm. Sci. 2013, 49, 679698,  DOI: 10.1016/j.ejps.2013.05.019
  57. 57
    Ding, X.; Rose, J. P.; Van Gelder, J. Developability assessment of clinical drug products with maximum absorbable doses. Int. J. Pharm. 2012, 427, 260269,  DOI: 10.1016/j.ijpharm.2012.02.003
  58. 58
    McGinnity, D. F.; Collington, J.; Austin, R. P.; Riley, R. J. Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs. Curr. Drug Metab. 2007, 8, 463479,  DOI: 10.2174/138920007780866799
  59. 59
    Sohlenius-Sternbeck, A. K.; Jones, C.; Ferguson, D.; Middleton, B. J.; Projean, D.; Floby, E.; Bylund, J.; Afzelius, L. Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes. Xenobiotica 2012, 42, 841853,  DOI: 10.3109/00498254.2012.669080
  60. 60
    Yap, T. A.; Krebs, M. G.; Postel-Vinay, S.; Bang, Y. J.; El-Khoueiry, A.; Abida, W.; Harrington, K.; Sundar, R.; Carter, L.; Castanon-Alvarez, E.; Im, S. A.; Berges, A.; Khan, M.; Stephens, C.; Ross, G.; Soria, J. C. Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers. Eur. J. Cancer 2016, 69, S2,  DOI: 10.1016/S0959-8049(16)32607-7
  61. 61
    Krebs, M. G.; Lopez, J.; El-Khoueiry, A.; Bang, Y.-J.; Postel-Vinay, S.; Abida, W.; Carter, L.; Xu, W.; Im, S.-A.; Pierce, A.; Frewer, P.; Berges, A.; Cheung, S. Y. A.; Stephens, C.; Felicetti, B.; Dean, E.; Hollingsworth, S. J. Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Proceedings of the American Association for Cancer Research Annual Meeting 2018, Chicago, IL, Apr 14–18, 2018; AACR: Philadelphia, PA, 2018;
    Cancer Res 2018, 78 (13, Suppl.), CT026, DOI: 10.1158/1538-7445.AM2018-CT026
  62. 62
    Berges, A.; Cheung, S. Y. A.; Pierce, A.; Dean, E.; Felicetti, B.; Standifer, N.; Smith, S.; Yates, J.; Lau, A.; Stephens, C.; Krebs, M. G.; Harrington, K.; Hollingsworth, S. J. PK-Biomarker-Safety modelling aids choice of recommended Phase II dose and schedule for AZD6738 (ATR inhibitor). Proceedings of the American Association for Cancer Research Annual Meeting 2018, Chicago, IL, Apr 14–18, 2018; AACR: Philadelphia, PA, 2018;
    Cancer Res. 2018, 78 (13, Suppl.), CT118,  DOI: 10.1158/1538-7445.AM2018-CT118
  63. 63
    Lloyd, R.; Falenta, K.; Wijnhoven, P. W.; Chabbert, C.; Stott, J.; Yates, J.; Lau, A. Y.; Young, L. A.; Hollingsworth, S. J. The PARP inhibitor olaparib is synergistic with the ATR inhibitor AZD6738 in ATM deficient cancer cells. Proceedings of the American Association for Cancer Research Annual Meeting 2018, Chicago, IL, Apr 14–18, 2018; AACR: Philadelphia, PA, 2018;
    Cancer Res. 2018, 78 (13, Suppl.), 337, DOI: 10.1158/1538-7445.AM2018-337

Cited By

ARTICLE SECTIONS
Jump To

This article is cited by 197 publications.

  1. Brittany C. Haas, Ngiap-Kie Lim, Janis Jermaks, Eden Gaster, Melody C. Guo, Thomas C. Malig, Jacob Werth, Haiming Zhang, F. Dean Toste, Francis Gosselin, Scott J. Miller, Matthew S. Sigman. Enantioselective Sulfonimidamide Acylation via a Cinchona Alkaloid-Catalyzed Desymmetrization: Scope, Data Science, and Mechanistic Investigation. Journal of the American Chemical Society 2024, 146 (12) , 8536-8546. https://doi.org/10.1021/jacs.4c00374
  2. W. Cameron Black, Abbas Abdoli, Xiuli An, Anick Auger, Patrick Beaulieu, Michel Bernatchez, Cathy Caron, Amandine Chefson, Sheldon Crane, Mohamed Diallo, Stéphane Dorich, Lee D. Fader, Gino B. Ferraro, Sara Fournier, Qi Gao, Yelena Ginzburg, Martine Hamel, Yongshuai Han, Paul Jones, Stéphanie Lanoix, Cyrus M. Lacbay, Marie-Eve Leclaire, Maayan Levy, Yael Mamane, Amina Mulani, Robert Papp, Charles Pellerin, Audrey Picard, Alexander Skeldon, Kathryn Skorey, Rino Stocco, Miguel St.-Onge, Jean-François Truchon, Vouy Linh Truong, Michal Zimmermann, Michael Zinda, Anne Roulston. Discovery of the Potent and Selective ATR Inhibitor Camonsertib (RP-3500). Journal of Medicinal Chemistry 2024, 67 (4) , 2349-2368. https://doi.org/10.1021/acs.jmedchem.3c01917
  3. Zhenhao Zhong, Tsz-Kan Ma, Andrew J. P. White, James A. Bull. Synthesis of Pyrazolesulfoximines Using α-Diazosulfoximines with Alkynes. Organic Letters 2024, 26 (6) , 1178-1183. https://doi.org/10.1021/acs.orglett.3c04274
  4. Emilie Werner, Milena Wiegand, Joseph Moran, David Lebœuf. Rapid Access to Densely Functionalized Cyclopentenyl Sulfoximines through a Sc-Catalyzed Aza-Piancatelli Reaction. Organic Letters 2024, 26 (2) , 547-552. https://doi.org/10.1021/acs.orglett.3c04095
  5. Nicholas A. Meanwell. Applications of Bioisosteres in the Design of Biologically Active Compounds. Journal of Agricultural and Food Chemistry 2023, 71 (47) , 18087-18122. https://doi.org/10.1021/acs.jafc.3c00765
  6. Matthew L. Condakes, Jennifer JiangDavid W. LinRhiannon Thomas-Tran, Juan del Pozo, Christiana N. Teijaro. NEW CHEMICAL ENTITIES ENTERING PHASE III TRIALS IN 2022. , 577-592. https://doi.org/10.1021/mc-2023-vol58.ch23
  7. Pei Xie, Yating Zheng, Yuping Luo, Jinyun Luo, Leifang Wu, Zhihua Cai, Lin He. Synthesis of Sulfilimines via Multicomponent Reaction of Arynes, Sulfamides, and Thiosulfonates. Organic Letters 2023, 25 (33) , 6133-6138. https://doi.org/10.1021/acs.orglett.3c02217
  8. John R. Swierk. The Cost of Quantum Yield. Organic Process Research & Development 2023, 27 (7) , 1411-1419. https://doi.org/10.1021/acs.oprd.3c00167
  9. Xianda Wu, Yuqing Li, Minghong Chen, Fu-Sheng He, Jie Wu. Metal-Free Chemoselective S-Arylation of Sulfenamides To Access Sulfilimines. The Journal of Organic Chemistry 2023, 88 (13) , 9352-9359. https://doi.org/10.1021/acs.joc.3c00961
  10. Dean G. Brown. An Analysis of Successful Hit-to-Clinical Candidate Pairs. Journal of Medicinal Chemistry 2023, 66 (11) , 7101-7139. https://doi.org/10.1021/acs.jmedchem.3c00521
  11. Gao-feng Yang, He-sen Huang, Xiao-kang Nie, Shi-qi Zhang, Xin Cui, Zhuo Tang, Guang-xun Li. One-Pot Tandem Oxidative Bromination and Amination of Sulfenamide for the Synthesis of Sulfinamidines. The Journal of Organic Chemistry 2023, 88 (7) , 4581-4591. https://doi.org/10.1021/acs.joc.3c00042
  12. Yue Chen, Dong-mei Fang, He-sen Huang, Xiao-kang Nie, Shi-qi Zhang, Xin Cui, Zhuo Tang, Guang-xun Li. Synthesis of Sulfilimines via Selective S–C Bond Formation in Water. Organic Letters 2023, 25 (12) , 2134-2138. https://doi.org/10.1021/acs.orglett.3c00604
  13. Xin Zhang, Fucheng Wang, Choon-Hong Tan. Asymmetric Synthesis of S(IV) and S(VI) Stereogenic Centers. JACS Au 2023, 3 (3) , 700-714. https://doi.org/10.1021/jacsau.2c00626
  14. Liansheng Liu, Yiying Liu, Shan Li, Jin Gao, Jing Li, Junfa Wei. Rh(III)-Catalyzed [4 + 1] Annulation of Sulfoximines with Maleimides: Access to Benzoisothiazole Spiropyrrolidinediones. The Journal of Organic Chemistry 2023, 88 (6) , 3626-3635. https://doi.org/10.1021/acs.joc.2c02811
  15. Gao-feng Yang, Yi Yuan, Yin Tian, Shi-qi Zhang, Xin Cui, Bing Xia, Guang-xun Li, Zhuo Tang. Synthesis of Chiral Sulfonimidoyl Chloride via Desymmetrizing Enantioselective Hydrolysis. Journal of the American Chemical Society 2023, 145 (9) , 5439-5446. https://doi.org/10.1021/jacs.2c13758
  16. Edna Mao, David W.C. MacMillan. Late-Stage C(sp3)–H Methylation of Drug Molecules. Journal of the American Chemical Society 2023, 145 (5) , 2787-2793. https://doi.org/10.1021/jacs.2c13396
  17. Minjie Xu, Zhou Lu, Zengrui Wu, Minyan Gui, Guixia Liu, Yun Tang, Weihua Li. Development of In Silico Models for Predicting Potential Time-Dependent Inhibitors of Cytochrome P450 3A4. Molecular Pharmaceutics 2023, 20 (1) , 194-205. https://doi.org/10.1021/acs.molpharmaceut.2c00571
  18. Zhenhao Zhong, Julian Chesti, Alan Armstrong, James A. Bull. Synthesis of Sulfoximine Propargyl Carbamates under Improved Conditions for Rhodium Catalyzed Carbamate Transfer to Sulfoxides. The Journal of Organic Chemistry 2022, 87 (23) , 16115-16126. https://doi.org/10.1021/acs.joc.2c02083
  19. Ryan M. Phelan, Michael J. Abrahamson, Jesse T. C. Brown, Ruijie K. Zhang, Christian R. Zwick, III. Development of Scalable Processes with Underutilized Biocatalyst Classes. Organic Process Research & Development 2022, 26 (7) , 1944-1959. https://doi.org/10.1021/acs.oprd.1c00467
  20. Rezaul Md Karim, Leixiang Yang, Lihong Chen, Melissa J. Bikowitz, Junhao Lu, Dylan Grassie, Zachary P. Shultz, Justin M. Lopchuk, Jiandong Chen, Ernst Schönbrunn. Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain. Journal of Medicinal Chemistry 2022, 65 (5) , 4182-4200. https://doi.org/10.1021/acs.jmedchem.1c01999
  21. Giampiero Proietti, Julius Kuzmin, Azamat Z. Temerdashev, Peter Dinér. Accessing Perfluoroaryl Sulfonimidamides and Sulfoximines via Photogenerated Perfluoroaryl Nitrenes: Synthesis and Application as a Chiral Auxiliary. The Journal of Organic Chemistry 2021, 86 (23) , 17119-17128. https://doi.org/10.1021/acs.joc.1c02241
  22. Edwin Alfonzo, Sudhir M. Hande. α-Heteroarylation of Thioethers via Photoredox and Weak Brønsted Base Catalysis. Organic Letters 2021, 23 (15) , 6115-6120. https://doi.org/10.1021/acs.orglett.1c02151
  23. Gregory B. Craven, Edward L. Briggs, Charlotte M. Zammit, Alexander McDermott, Stephanie Greed, Dominic P. Affron, Charlotte Leinfellner, Hannah R. Cudmore, Ruth R. Tweedy, Renzo Luisi, James A. Bull, Alan Armstrong. Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides. The Journal of Organic Chemistry 2021, 86 (11) , 7403-7424. https://doi.org/10.1021/acs.joc.1c00373
  24. Andreas Dannhorn, Stephanie Ling, Steven Powell, Eileen McCall, Gareth Maglennon, Gemma N. Jones, Andrew J. Pierce, Nicole Strittmatter, Gregory Hamm, Simon T. Barry, Josephine Bunch, Richard J. A. Goodwin, Zoltan Takats. Evaluation of UV-C Decontamination of Clinical Tissue Sections for Spatially Resolved Analysis by Mass Spectrometry Imaging (MSI). Analytical Chemistry 2021, 93 (5) , 2767-2775. https://doi.org/10.1021/acs.analchem.0c03430
  25. Mark A. Graham, Hannah Askey, Andrew D. Campbell, Lai Chan, Katie G. Cooper, Zhaoshan Cui, Andrew Dalgleish, David Dave, Gareth Ensor, Maria Rita Galan Espinosa, Peter Hamilton, Claire Heffernan, Lucinda V. Jackson, Dajiang Jing, Martin F. Jones, Pengpeng Liu, Keith R. Mulholland, Mohammed Pervez, Michael Popadynec, Emma Randles, Simone Tomasi, Shenghua Wang. Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib. Organic Process Research & Development 2021, 25 (1) , 43-56. https://doi.org/10.1021/acs.oprd.0c00482
  26. Mark A. Graham, Gary Noonan, Janette H. Cherryman, James J. Douglas, Miguel Gonzalez, Lucinda V. Jackson, Kevin Leslie, Zhi-qing Liu, David McKinney, Rachel H. Munday, Chris D. Parsons, David T. E. Whittaker, En-xuan Zhang, Jun-wang Zhang. Development and Proof of Concept for a Large-Scale Photoredox Additive-Free Minisci Reaction. Organic Process Research & Development 2021, 25 (1) , 57-67. https://doi.org/10.1021/acs.oprd.0c00483
  27. Samuel H. Myers, Jose Antonio Ortega, Andrea Cavalli. Synthetic Lethality through the Lens of Medicinal Chemistry. Journal of Medicinal Chemistry 2020, 63 (23) , 14151-14183. https://doi.org/10.1021/acs.jmedchem.0c00766
  28. Patrick Mäder, Lars Kattner. Sulfoximines as Rising Stars in Modern Drug Discovery? Current Status and Perspective on an Emerging Functional Group in Medicinal Chemistry. Journal of Medicinal Chemistry 2020, 63 (23) , 14243-14275. https://doi.org/10.1021/acs.jmedchem.0c00960
  29. Junheng Liu, Guangyang Xu, Shengbiao Tang, Qun Chen, Jiangtao Sun. Site-Selective Functionalization of 7-Azaindoles via Carbene Transfer and Isolation of N-Aromatic Zwitterions. Organic Letters 2020, 22 (23) , 9376-9380. https://doi.org/10.1021/acs.orglett.0c03653
  30. Peng Shi, Yongliang Tu, Chenyang Wang, Deshen Kong, Ding Ma, Carsten Bolm. Synthesis of Benzothiadiazine-1-oxides by Rhodium-Catalyzed C−H Amidation/Cyclization. Organic Letters 2020, 22 (22) , 8842-8845. https://doi.org/10.1021/acs.orglett.0c03212
  31. Edwin Alfonzo, Sudhir M. Hande. Photoredox and Weak Brønsted Base Dual Catalysis: Alkylation of α-Thio Alkyl Radicals. ACS Catalysis 2020, 10 (21) , 12590-12595. https://doi.org/10.1021/acscatal.0c03851
  32. Bianca Altenburg, Marcus Frings, Jan-Hendrik Schöbel, Jonas Goßen, Kristina Pannen, Kim Vanderliek, Giulia Rossetti, Steffen Koschmieder, Nicolas Chatain, Carsten Bolm. Chiral Analogues of PFI-1 as BET Inhibitors and Their Functional Role in Myeloid Malignancies. ACS Medicinal Chemistry Letters 2020, 11 (10) , 1928-1934. https://doi.org/10.1021/acsmedchemlett.9b00625
  33. Shan Li, Liansheng Liu, Rong Wang, Yihui Yang, Jing Li, Junfa Wei. Palladium-Catalyzed Oxidative Annulation of Sulfoximines and Arynes by C–H Functionalization as an Approach to Dibenzothiazines. Organic Letters 2020, 22 (19) , 7470-7474. https://doi.org/10.1021/acs.orglett.0c02615
  34. Thomas Q. Davies, Michael J. Tilby, Jack Ren, Nicholas A. Parker, David Skolc, Adrian Hall, Fernanda Duarte, Michael C. Willis. Harnessing Sulfinyl Nitrenes: A Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides. Journal of the American Chemical Society 2020, 142 (36) , 15445-15453. https://doi.org/10.1021/jacs.0c06986
  35. Peter Ertl, Eva Altmann, Jeffrey M. McKenna. The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time. Journal of Medicinal Chemistry 2020, 63 (15) , 8408-8418. https://doi.org/10.1021/acs.jmedchem.0c00754
  36. Ulrich Lücking, Lars Wortmann, Antje M. Wengner, Julien Lefranc, Philip Lienau, Hans Briem, Gerhard Siemeister, Ulf Bömer, Karsten Denner, Martina Schäfer, Marcus Koppitz, Knut Eis, Florian Bartels, Benjamin Bader, Wilhelm Bone, Dieter Moosmayer, Simon J. Holton, Uwe Eberspächer, Joanna Grudzinska-Goebel, Christoph Schatz, Gesa Deeg, Dominik Mumberg, Franz von Nussbaum. Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models. Journal of Medicinal Chemistry 2020, 63 (13) , 7293-7325. https://doi.org/10.1021/acs.jmedchem.0c00369
  37. Sang Mee Kim, On-Yu Kang, Hwan Jung Lim, Seong Jun Park. Selective Synthesis of N-Cyano Sulfilimines by Dearomatizing Stable Thionium Ions. ACS Omega 2020, 5 (17) , 10191-10199. https://doi.org/10.1021/acsomega.0c01086
  38. Priscilla Mendonça Matos, William Lewis, Stephen P. Argent, Jonathan C. Moore, Robert A. Stockman. General Method for the Asymmetric Synthesis of N–H Sulfoximines via C–S Bond Formation. Organic Letters 2020, 22 (7) , 2776-2780. https://doi.org/10.1021/acs.orglett.0c00761
  39. William R. F. Goundry, Kuangchu Dai, Miguel Gonzalez, Daniel Legg, Anne O’Kearney-McMullan, James Morrison, Andrew Stark, Paul Siedlecki, Paula Tomlin, Jianbo Yang. Development and Scale-up of a Route to ATR Inhibitor AZD6738. Organic Process Research & Development 2019, 23 (7) , 1333-1342. https://doi.org/10.1021/acs.oprd.9b00075
  40. Ronald Knegtel, Jean-Damien Charrier, Steven Durrant, Chris Davis, Michael O’Donnell, Pierre Storck, Somhairle MacCormick, David Kay, Joanne Pinder, Anisa Virani, Heather Twin, Matthew Griffiths, Philip Reaper, Peter Littlewood, Steve Young, Julian Golec, John Pollard. Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor. Journal of Medicinal Chemistry 2019, 62 (11) , 5547-5561. https://doi.org/10.1021/acs.jmedchem.9b00426
  41. Bram Verbelen, Eric Siemes, Andreas Ehnbom, Christoph Räuber, Kari Rissanen, Dominik Wöll, Carsten Bolm. From One-Pot NH-Sulfoximidations of Thiophene Derivatives to Dithienylethene-Type Photoswitches. Organic Letters 2019, 21 (11) , 4293-4297. https://doi.org/10.1021/acs.orglett.9b01475
  42. Zhen Li, Marcus Frings, Hao Yu, Carsten Bolm. Organocatalytic Synthesis of Sulfoximidoyl-Containing Carbamates from Sulfoximines and Morita–Baylis–Hillman Carbonates. Organic Letters 2019, 21 (9) , 3119-3122. https://doi.org/10.1021/acs.orglett.9b00772
  43. Elizabeth L. Hardaker, Emilio Sanseviero, Ankur Karmokar, Devon Taylor, Marta Milo, Chrysis Michaloglou, Adina Hughes, Mimi Mai, Matthew King, Anisha Solanki, Lukasz Magiera, Ricardo Miragaia, Gozde Kar, Nathan Standifer, Michael Surace, Shaan Gill, Alison Peter, Sara Talbot, Sehmus Tohumeken, Henderson Fryer, Ali Mostafa, Kathy Mulgrew, Carolyn Lam, Scott Hoffmann, Daniel Sutton, Larissa Carnevalli, Fernando J. Calero-Nieto, Gemma N. Jones, Andrew J. Pierce, Zena Wilson, David Campbell, Lynet Nyoni, Carla P. Martins, Tamara Baker, Gilberto Serrano de Almeida, Zainab Ramlaoui, Abdel Bidar, Benjamin Phillips, Joseph Boland, Sonia Iyer, J. Carl Barrett, Arsene-Bienvenu Loembé, Serge Y. Fuchs, Umamaheswar Duvvuri, Pei-Jen Lou, Melonie A. Nance, Carlos Alberto Gomez Roca, Elaine Cadogan, Susan E. Critichlow, Steven Fawell, Mark Cobbold, Emma Dean, Viia Valge-Archer, Alan Lau, Dmitry I. Gabrilovich, Simon T. Barry. The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment. Nature Communications 2024, 15 (1) https://doi.org/10.1038/s41467-024-45996-4
  44. John J. Monteith, James W. Pearson, Sophie A. L. Rousseaux. Photocatalytic O ‐ to S ‐Rearrangement of Tertiary Cyclopropanols. Angewandte Chemie 2024, 136 (17) https://doi.org/10.1002/ange.202402912
  45. Yubo Wang, Ruonan Wang, Yanli Zhao, Sheng Cao, Chen Li, Yanjie Wu, Lan Ma, Ying Liu, Yuhong Yao, Yue Jiao, Yukun Chen, Shuangwei Liu, Kun Zhang, Mingming Wei, Cheng Yang, Guang Yang. Discovery of Selective and Potent ATR Degrader for Exploration its Kinase‐Independent Functions in Acute Myeloid Leukemia Cells. Angewandte Chemie 2024, 136 (17) https://doi.org/10.1002/ange.202318568
  46. Yubo Wang, Ruonan Wang, Yanli Zhao, Sheng Cao, Chen Li, Yanjie Wu, Lan Ma, Ying Liu, Yuhong Yao, Yue Jiao, Yukun Chen, Shuangwei Liu, Kun Zhang, Mingming Wei, Cheng Yang, Guang Yang. Discovery of Selective and Potent ATR Degrader for Exploration its Kinase‐Independent Functions in Acute Myeloid Leukemia Cells. Angewandte Chemie International Edition 2024, 63 (17) https://doi.org/10.1002/anie.202318568
  47. John J. Monteith, James W. Pearson, Sophie A. L. Rousseaux. Photocatalytic O ‐ to S ‐Rearrangement of Tertiary Cyclopropanols. Angewandte Chemie International Edition 2024, 63 (17) https://doi.org/10.1002/anie.202402912
  48. Lei Huang, Jialu Shao, Wenwen Lai, Hongfeng Gu, Jieping Yang, Shi Shi, Shepherd Wufoyrwoth, Zhe Song, Yi Zou, Yungen Xu, Qihua Zhu. Discovery of the first ataxia telangiectasia and Rad3-related (ATR) degraders for cancer treatment. European Journal of Medicinal Chemistry 2024, 267 , 116159. https://doi.org/10.1016/j.ejmech.2024.116159
  49. Benjamin Besse, Elvire Pons-Tostivint, Keunchil Park, Sylvia Hartl, Patrick M. Forde, Maximilian J. Hochmair, Mark M. Awad, Michael Thomas, Glenwood Goss, Paul Wheatley-Price, Frances A. Shepherd, Marie Florescu, Parneet Cheema, Quincy S. C. Chu, Sang-We Kim, Daniel Morgensztern, Melissa L. Johnson, Sophie Cousin, Dong-Wan Kim, Mor T. Moskovitz, David Vicente, Boaz Aronson, Rosalind Hobson, Helen J. Ambrose, Sajan Khosla, Avinash Reddy, Deanna L. Russell, Mohamed Reda Keddar, James P. Conway, J. Carl Barrett, Emma Dean, Rakesh Kumar, Marlene Dressman, Philip J. Jewsbury, Sonia Iyer, Simon T. Barry, Jan Cosaert, John V. Heymach. Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial. Nature Medicine 2024, 30 (3) , 716-729. https://doi.org/10.1038/s41591-024-02808-y
  50. Minghong Liao, Yonggui Liu, Hongyan Long, Qin Xiong, Xiaokang Lv, Zhongfu Luo, Xingxing Wu, Yonggui Robin Chi. Enantioselective sulfinylation of alcohols and amines by condensation with sulfinates. Chem 2024, 16 https://doi.org/10.1016/j.chempr.2024.02.016
  51. Shun Teng, Zachary P. Shultz, Chuan Shan, Lukasz Wojtas, Justin M. Lopchuk. Asymmetric synthesis of sulfoximines, sulfonimidoyl fluorides and sulfonimidamides enabled by an enantiopure bifunctional S(VI) reagent. Nature Chemistry 2024, 16 (2) , 183-192. https://doi.org/10.1038/s41557-023-01419-3
  52. Magnus T. Dillon, Jeane Guevara, Kabir Mohammed, Emmanuel C. Patin, Simon A. Smith, Emma Dean, Gemma N. Jones, Sophie E. Willis, Marcella Petrone, Carlos Silva, Khin Thway, Catey Bunce, Ioannis Roxanis, Pablo Nenclares, Anna Wilkins, Martin McLaughlin, Adoracion Jayme-Laiche, Sarah Benafif, Georgios Nintos, Vineet Kwatra, Lorna Grove, David Mansfield, Paula Proszek, Philip Martin, Luiza Moore, Karen E. Swales, Udai Banerji, Mark P. Saunders, James Spicer, Martin D. Forster, Kevin J. Harrington. Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. Journal of Clinical Investigation 2024, 134 (2) https://doi.org/10.1172/JCI175369
  53. Xianda Wu, Minghong Chen, Shuiyun Zheng, Fu-Sheng He, Jie Wu. Iron-catalyzed sulfur alkylation of sulfenamides with in situ-generated 2,2,2-trifluorodiazoethane. Journal of Fluorine Chemistry 2024, 273 , 110219. https://doi.org/10.1016/j.jfluchem.2023.110219
  54. Alvina I. Khamidullina, Yaroslav E. Abramenko, Alexandra V. Bruter, Victor V. Tatarskiy. Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets. International Journal of Molecular Sciences 2024, 25 (2) , 1263. https://doi.org/10.3390/ijms25021263
  55. Ayan Acharya, Mukul Yadav, Mithilesh Nagpure, Sanathanalaxmi Kumaresan, Sankar K. Guchhait. Molecular medicinal insights into scaffold hopping-based drug discovery success. Drug Discovery Today 2024, 29 (1) , 103845. https://doi.org/10.1016/j.drudis.2023.103845
  56. Yinsong Wu, Guanghao Shi, Yanan Liu, Yangzilin Kong, Mengdi Wu, Demao Wang, Xiaobing Wu, Yongjia Shang, Xinwei He. A rhodium-catalyzed cascade C–H activation/annulation strategy for the expeditious assembly of pyrrolidinedione-fused 1,2-benzothiazines. Organic & Biomolecular Chemistry 2024, 126 https://doi.org/10.1039/D4OB00193A
  57. Norie Sugitani, Hannah R. Mason, Brian T. Campfield, Jon D. Piganelli. An orally available cancer drug AZD6738 prevents type 1 diabetes. Frontiers in Immunology 2023, 14 https://doi.org/10.3389/fimmu.2023.1290058
  58. Qi Li, Wenyuan Qian, Yang Zhang, Lihong Hu, Shuhui Chen, Yuanfeng Xia. A new wave of innovations within the DNA damage response. Signal Transduction and Targeted Therapy 2023, 8 (1) https://doi.org/10.1038/s41392-023-01548-8
  59. Ting Wang, Zhi-Huan Peng, Liexin Wu, Qingwei Song, Qianying Li, Hui Gao, Zhongyi Zeng, Zhi Zhou, Wei Yi. Rh( iii )-catalyzed redox-neutral C–H [4 + 1] annulation of sulfoximines with α,α-difluoromethylene alkynes: diastereoselective synthesis of E -monofluoroalkenyl benzoisothiazole 1-oxides. Organic Chemistry Frontiers 2023, 10 (23) , 5916-5922. https://doi.org/10.1039/D3QO01263H
  60. Xianda Wu, Minghong Chen, Fu-Sheng He, Jie Wu. Synthesis of functionalized sulfilimines via iron-catalyzed sulfur alkylation of sulfenamides with diazo compounds. Green Chemistry 2023, 25 (22) , 9092-9096. https://doi.org/10.1039/D3GC03528J
  61. Wenwei Liu, Wei Feng, Yongxin Zhang, Tianxiang Lei, Xiaofeng Wang, Tang Qiao, Zehong Chen, Wu Song. RP11-789C1.1 inhibits gastric cancer cell proliferation and accelerates apoptosis via the ATR/CHK1 signaling pathway. Chinese Medical Journal 2023, 71 https://doi.org/10.1097/CM9.0000000000002869
  62. Min Han, Lanxin Luo, Zhuo Tang, Guang-xun Li, Qiwei Wang. Synthesis of Sulfoximines through Selective Sulfur Alkylation of Sulfinamides Generated In Situ from β-Sulfoximine Esters. Synlett 2023, 34 (15) , 1829-1833. https://doi.org/10.1055/a-2063-4992
  63. Atsushi Umehara, Soma Shimizu, Makoto Sasaki. Synthesis of Bulky N ‐Acyl Heterocycles by DMAPO/Boc 2 O‐Mediated One‐Pot Direct N ‐Acylation of Less Nucleophilic N ‐Heterocycles with α‐Fully Substituted Carboxylic Acids. Advanced Synthesis & Catalysis 2023, 365 (14) , 2367-2376. https://doi.org/10.1002/adsc.202300487
  64. Jinal A Patel, Camryn Zezelic, Julie Rageul, Joanne Saldanha, Arafat Khan, Hyungjin Kim. Replisome dysfunction upon inducible TIMELESS degradation synergizes with ATR inhibition to trigger replication catastrophe. Nucleic Acids Research 2023, 51 (12) , 6246-6263. https://doi.org/10.1093/nar/gkad363
  65. Yimin Qin, Zhenqiang Zhang, Xinyi Ye, Choon‐Hong Tan. Ion Pair Catalyst ‐ Pentanidinium. The Chemical Record 2023, 23 (7) https://doi.org/10.1002/tcr.202200304
  66. Lewis D. Pennington, Philip N. Collier, Eamon Comer. Harnessing the necessary nitrogen atom in chemical biology and drug discovery. Medicinal Chemistry Research 2023, 32 (7) , 1278-1293. https://doi.org/10.1007/s00044-023-03073-3
  67. Yunxin Duan, Haodong Cheng, Lili Zhuang, Jiawei Xia, Yerong Xu, Ruyue Zhang, Rui Sun, Tao Lu, Yadong Chen. Discovery of Thieno[3,2-d]pyrimidine derivatives as potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) kinase. European Journal of Medicinal Chemistry 2023, 255 , 115370. https://doi.org/10.1016/j.ejmech.2023.115370
  68. Yunxin Duan, Lili Zhuang, Yerong Xu, Haodong Cheng, Jiawei Xia, Tao Lu, Yadong Chen. Design, synthesis, and biological evaluation of pyrido[3,2-d]pyrimidine derivatives as novel ATR inhibitors. Bioorganic Chemistry 2023, 136 , 106535. https://doi.org/10.1016/j.bioorg.2023.106535
  69. Cayden J. Dodd, Daniel C. Schultz, Jinming Li, Craig W. Lindsley, Aaron M. Bender. Alkylation of N H-sulfoximines under Mitsunobu-type conditions. Organic & Biomolecular Chemistry 2023, 21 (25) , 5181-5184. https://doi.org/10.1039/D3OB00810J
  70. Sadaf Fatima, Almaz Zaki, Hari Madhav, Bibi Shaguftah Khatoon, Abdur Rahman, Mohd Wasif Manhas, Nasimul Hoda, Syed Mansoor Ali. Design, synthesis, and biological evaluation of morpholinopyrimidine derivatives as anti-inflammatory agents. RSC Advances 2023, 13 (28) , 19119-19129. https://doi.org/10.1039/D3RA01893H
  71. Jialu Shao, Lei Huang, Wenwen Lai, Yi Zou, Qihua Zhu. Design, Synthesis, and Biological Evaluation of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase for the Efficient Treatment of Cancer. Molecules 2023, 28 (11) , 4521. https://doi.org/10.3390/molecules28114521
  72. Rui Zhang, Chang‐Yang Song, Zhe Sui, Ye Yuan, Yu‐Cheng Gu, Cheng Chen. Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions. The Chemical Record 2023, 23 (5) https://doi.org/10.1002/tcr.202300020
  73. Hye Ryeong Jun, Hyun Ju Kang, Sung Hun Ju, Jung Eun Kim, Sang Youl Jeon, Bosung Ku, Jae Jun Lee, Minsung Kim, Min Jeong Kim, Jung-Joo Choi, Joseph J. Noh, Hyun-Soo Kim, Jeong-Won Lee, Jin-Ku Lee, Dong Woo Lee. High-throughput organo-on-pillar (high-TOP) array system for three-dimensional ex vivo drug testing. Biomaterials 2023, 296 , 122087. https://doi.org/10.1016/j.biomaterials.2023.122087
  74. Renè Hommelsheim, Sandra Bausch, Robin van Nahl, Jas S. Ward, Kari Rissanen, Carsten Bolm. Synthesis of 3-amino-substituted benzothiadiazine oxides by a palladium-catalysed cascade reaction. Green Chemistry 2023, 25 (8) , 3021-3026. https://doi.org/10.1039/D3GC00442B
  75. Zenghui Ye, Xi Zhang, Weiyuan Ma, Fengzhi Zhang. Advances in S–N bond formation via electrochemistry: a green route utilizing diverse sulfur and nitrogen sources. Green Chemistry 2023, 25 (7) , 2524-2540. https://doi.org/10.1039/D3GC00175J
  76. Frank P. Vendetti, Pinakin Pandya, David A. Clump, Sandra Schamus-Haynes, Meysam Tavakoli, Maria diMayorca, Naveed M. Islam, Jina Chang, Greg M. Delgoffe, Jan H. Beumer, Christopher J. Bakkenist. The schedule of ATR inhibitor AZD6738 can potentiate or abolish antitumor immune responses to radiotherapy. JCI Insight 2023, 8 (4) https://doi.org/10.1172/jci.insight.165615
  77. Shu‐Yong Song, Xiaoyu Zhou, Zhuofeng Ke, Senmiao Xu. Synthesis of Chiral Sulfoximines via Iridium‐Catalyzed Regio‐ and Enantioselective C−H Borylation: A Remarkable Sidearm Effect of Ligand. Angewandte Chemie 2023, 135 (6) https://doi.org/10.1002/ange.202217130
  78. Shu‐Yong Song, Xiaoyu Zhou, Zhuofeng Ke, Senmiao Xu. Synthesis of Chiral Sulfoximines via Iridium‐Catalyzed Regio‐ and Enantioselective C−H Borylation: A Remarkable Sidearm Effect of Ligand. Angewandte Chemie International Edition 2023, 62 (6) https://doi.org/10.1002/anie.202217130
  79. Florian J. Groelly, Matthew Fawkes, Rebecca A. Dagg, Andrew N. Blackford, Madalena Tarsounas. Targeting DNA damage response pathways in cancer. Nature Reviews Cancer 2023, 23 (2) , 78-94. https://doi.org/10.1038/s41568-022-00535-5
  80. Renzo Luisi, James A. Bull. Synthesis of Sulfoximines and Sulfonimidamides Using Hypervalent Iodine Mediated NH Transfer. Molecules 2023, 28 (3) , 1120. https://doi.org/10.3390/molecules28031120
  81. Shinnosuke Harata, Takuya Suzuki, Hiroki Takahashi, Takahisa Hirokawa, Akira Kato, Kaori Watanabe, Takeshi Yanagita, Hajime Ushigome, Kazuyoshi Shiga, Ryo Ogawa, Akira Mitsui, Masahiro Kimura, Yoichi Matsuo, Shuji Takiguchi. AZD6738 promotes the tumor suppressive effects of trifluridine in colorectal cancer cells. Oncology Reports 2023, 49 (3) https://doi.org/10.3892/or.2023.8489
  82. On-Yu Kang, Eunsil Kim, Won Hyung Lee, Do Hyun Ryu, Hwan Jung Lim, Seong Jun Park. N -Cyano sulfilimine functional group as a nonclassical amide bond bioisostere in the design of a potent analogue to anthranilic diamide insecticide. RSC Advances 2023, 13 (3) , 2004-2009. https://doi.org/10.1039/D2RA06988A
  83. Kevin J. Harrington, Charleen M. L. Chan Wah Hak, Antonio Rullan, Emmanuel Patin. DNA Repair Mechanisms as a New Target in Head and Neck Cancer. 2023, 23-35. https://doi.org/10.1007/978-3-031-23175-9_3
  84. Mariana Pereira, Bárbara Costa, Nuno Vale. Targeting DNA damage response pathways in glioblastoma: From mechanistic insights to advances in the clinic. 2023, 345-360. https://doi.org/10.1016/B978-0-323-99873-4.00017-7
  85. Yinliang Qi, Kun Wang, Bin Long, Hao Yue, Yongshuo Wu, Dexiao Yang, Minghui Tong, Xuan Shi, Yunlei Hou, Yanfang Zhao. Discovery of novel 7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines as ATR inhibitors based on structure-based drug design. European Journal of Medicinal Chemistry 2023, 246 , 114945. https://doi.org/10.1016/j.ejmech.2022.114945
  86. 浩东 程. Advances in the Study of Small Molecule Inhibitors of ATR. Pharmacy Information 2023, 12 (02) , 138-156. https://doi.org/10.12677/PI.2023.122018
  87. Carolina Salguero, Christian Valladolid, Helen M. R. Robinson, Graeme C. M. Smith, Timothy A. Yap. Targeting ATR in Cancer Medicine. 2023, 239-283. https://doi.org/10.1007/978-3-031-30065-3_14
  88. Emily M. Schleicher, George‐Lucian Moldovan. CRISPR screens guide the way for PARP and ATR inhibitor biomarker discovery. The FEBS Journal 2022, 289 (24) , 7854-7868. https://doi.org/10.1111/febs.16217
  89. Leon Emanuel Schnöller, Valerie Albrecht, Nikko Brix, Alexander Edward Nieto, Daniel Felix Fleischmann, Maximilian Niyazi, Julia Hess, Claus Belka, Kristian Unger, Kirsten Lauber, Michael Orth. Integrative analysis of therapy resistance and transcriptomic profiling data in glioblastoma cells identifies sensitization vulnerabilities for combined modality radiochemotherapy. Radiation Oncology 2022, 17 (1) https://doi.org/10.1186/s13014-022-02052-z
  90. Zijie Gao, Jianye Xu, Yang Fan, Zongpu Zhang, Huizhi Wang, Mingyu Qian, Ping Zhang, Lin Deng, Jie Shen, Hao Xue, Rongrong Zhao, Teng Zhou, Xing Guo, Gang Li. ARPC1B promotes mesenchymal phenotype maintenance and radiotherapy resistance by blocking TRIM21-mediated degradation of IFI16 and HuR in glioma stem cells. Journal of Experimental & Clinical Cancer Research 2022, 41 (1) https://doi.org/10.1186/s13046-022-02526-8
  91. Ulrich Lücking. New Opportunities for the Utilization of the Sulfoximine Group in Medicinal Chemistry from the Drug Designer's Perspective**. Chemistry – A European Journal 2022, 28 (56) https://doi.org/10.1002/chem.202201993
  92. Lukas Gorecki, Darina Muthna, Sara Merdita, Martin Andrs, Tomas Kucera, Radim Havelek, Lubica Muckova, Tereza Kobrlova, Jiri Soukup, Petr Krupa, Lukas Prchal, Ondrej Soukup, Jaroslav Roh, Martina Rezacova, Jan Korabecny. 7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties. European Journal of Medicinal Chemistry 2022, 240 , 114580. https://doi.org/10.1016/j.ejmech.2022.114580
  93. Norie Sugitani, Frank P. Vendetti, Andrew J. Cipriano, Pinakin Pandya, Joshua J. Deppas, Tatiana N. Moiseeva, Sandra Schamus-Haynes, Yiyang Wang, Drake Palmer, Hatice U. Osmanbeyoglu, Anna Bostwick, Nathaniel W. Snyder, Yi-Nan Gong, Katherine M. Aird, Greg M. Delgoffe, Jan H. Beumer, Christopher J. Bakkenist. Thymidine rescues ATR kinase inhibitor-induced deoxyuridine contamination in genomic DNA, cell death, and interferon-α/β expression. Cell Reports 2022, 40 (12) , 111371. https://doi.org/10.1016/j.celrep.2022.111371
  94. Charleen M. L. Chan Wah Hak, Antonio Rullan, Emmanuel C. Patin, Malin Pedersen, Alan A. Melcher, Kevin J. Harrington. Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy. Frontiers in Oncology 2022, 12 https://doi.org/10.3389/fonc.2022.971959
  95. Fangliang Zhang, Liang Chen. Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations. Biomedicines 2022, 10 (8) , 1972. https://doi.org/10.3390/biomedicines10081972
  96. Min Han, Zhuo Tang, Guang-xun Li, Qi-wei Wang. Electrochemical oxidation chemoselective sulfimidation of thioether with sulfonamide via catalytic iodobenzene. Tetrahedron Letters 2022, 102 , 153925. https://doi.org/10.1016/j.tetlet.2022.153925
  97. Zhiquan Wang, Huihuang Yan, Justin C. Boysen, Charla R. Secreto, Renee C. Tschumper, Dania Ali, Qianqian Guo, Jian Zhong, Jiaqi Zhou, Haiyun Gan, Chuanhe Yu, Diane F. Jelinek, Susan L. Slager, Sameer A. Parikh, Esteban Braggio, Neil E. Kay. B cell receptor signaling drives APOBEC3 expression via direct enhancer regulation in chronic lymphocytic leukemia B cells. Blood Cancer Journal 2022, 12 (7) https://doi.org/10.1038/s41408-022-00690-w
  98. Weicai Huang, Zhen Han, Zepang Sun, Hao Feng, Liying Zhao, Qingyu Yuan, Chuanli Chen, Shitong Yu, Yanfeng Hu, Jiang Yu, Hao Liu, Guoxin Li, Yuming Jiang. PAK6 promotes homologous-recombination to enhance chemoresistance to oxaliplatin through ATR/CHK1 signaling in gastric cancer. Cell Death & Disease 2022, 13 (7) https://doi.org/10.1038/s41419-022-05118-8
  99. Sofia Zanotti, Bieke Decaesteker, Suzanne Vanhauwaert, Bram De Wilde, Winnok H. De Vos, Frank Speleman. Cellular senescence in neuroblastoma. British Journal of Cancer 2022, 126 (11) , 1529-1538. https://doi.org/10.1038/s41416-022-01755-0
  100. Muhamad Mustafa, Jean-Yves Winum. The importance of sulfur-containing motifs in drug design and discovery. Expert Opinion on Drug Discovery 2022, 17 (5) , 501-512. https://doi.org/10.1080/17460441.2022.2044783
Load all citations
  • Abstract

    Scheme 1

    Scheme 1. ATR Inhibitorsa

    a2, 3, and 4 are undergoing clinical testing.

    Scheme 2

    Scheme 2. a

    aReagents. (a) Compound 40: (Ph3P)4Pd, 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, Cs2CO3, 1,4-dioxane, water, rt. Compounds 41 and 42: 8-oxa-3-azabicyclo[3.2.1]octane or 3-oxa-8-azabicyclo[3.2.1]octane respectively, Et3N, DCM, rt. (b) Compound 43: 1,2-dibromoethane, NaH, DMF, 0 °C → rt. Compounds 44 and 45: 1,2-dibromoethane, 50% NaOH (aq), tetraoctylammonium bromide, DCM, rt. (c) Compound 7: (Ph3P)2PdCl2, 1H-indol-4-ylboronic acid, Na2CO3 (aq), 4:1 DME/water, microwave, 110 °C. Compounds 17 and 18: (Ph3P)4Pd, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine, Na2CO3 (aq), 1,4-dioxane, 95 °C.

    Scheme 3

    Scheme 3. a

    aReagents. (a) Compound 11: (Ph3P)4Pd, 1H-pyrrolo[2,3-b]pyridine-4-ylboronic acid, Na2CO3 (aq), 1,4-dioxane, 90 °C. Compound 12: 1H-benzo[d]imidazol-2-amine, Na2CO3, DMA, 160 °C, microwave. Compound 13: (Ph3P)2PdCl2, 1H-pyrrolo[2,3-b]pyridine-4-ylboronic acid, Na2CO3 (aq), 4:1 DME:water, 110 °C, microwave. Compound 14: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, bis(dibenzylideneacetone)palladium(0), 4-bromo-1H-pyrrolo[2,3-c]pyridine, KOAc, bis(pinacolato)diboron, dioxane, 100 °C followed by compound 46, (Ph3P)4Pd, Na2CO3 (aq), 100 °C. Compound 15: 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium, 4-bromo-1H-pyrrolo[2,3-c]pyridine, KOAc, bis(pinacolato)diboron, dioxane, 95 °C followed by compound 47, (Ph3P)4Pd, Na2CO3 (aq), 95 °C. Compound 16: (Ph3P)4Pd, Na2CO3 (aq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine, dioxane, 95 °C.

    Scheme 4

    Scheme 4. a

    aReagents: (a) 1,2-dibromoethane, 50% NaOH (aq), tetraoctylammonium bromide, toluene, 60 °C; (b) (R)-3-methylmorpholine, DIPEA, 1,4-dioxane, 80 °C; (c) NaO4W·2H2O, Bu4NHSO4, EtOAc, H2O2, 0 °C → rt. (d) Compound 19: 1H-benzo[d]imidazol-2-amine, Cs2CO3, DMA, 110 °C, microwave. Compound 21: N-methyl-1H-benzo[d]imidazol-2-amine, Cs2CO3, DMA, 90 °C. (e) DMAP, Ac2O, 90 °C.

    Scheme 5

    Scheme 5. a

    aReagents: (a) substituted 2-nitroaniline, Pd(OAc)2, Xantphos, Cs2CO3, 1,4-dioxane, 80 °C, microwave; (b) Zn, AcOH, rt or In, NH4Cl (aq), EtOH, reflux; (c) cyanogen bromide, MeOH, rt.

    Scheme 6

    Scheme 6. a

    aReagents: (a) NaSMe, DMF, rt; (b) NaIO4, EtOAc, MeOH, H2O, rt; (c) 1,2-dibromoethane, 50% NaOH (aq), tetraoctylammonium bromide, 2-Me-THF, 60 °C; (d) X-Phos second generation precatalyst, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, Cs2CO3, 1,4-dioxane/H2O (4:1), 90 °C; (e) trifluoroacetamide, iodobenzene diacetate, Rh(OAc)2 dimer, MgO, isopropylacetate, 80 °C; then 7 M NH3 in MeOH, rt; (f) NaOH (50% aq), 1,2-dibromoethane, tetraoctylammonium bromide, mTHF, rt. (g) Compound 33: (Ph3P)2PdCl2, 2 M Na2CO3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine, DME/H2O (4:1), 90 °C, then 2 M NaOH (aq), 50 °C. Compound 34: 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid, (Ph3P)2PdCl2, 2 M Na2CO3, DME/H2O (4:1), 90 °C. Compounds 35 and 36: Cs2CO3, N-methyl-1H-benzo[d]imidazol-2-amine, DMA, 80 °C.

    Figure 1

    Figure 1. Small-molecule crystal structures of 1 and 2. Short contacts of sulfonomethyl (left-hand panel) and azaindole (right-hand panel) moieties are indicated by dotted lines.

    Figure 2

    Figure 2. Sulfone and sulfoximine matched-pairs: (a, upper-left) ATR cell pIC50; (b, upper-right) log D7.4; (c, lower-left) hERG pIC50; (d, lower-right) aqueous solubility. Numbers refer to the compounds shown in Tables 25.

    Figure 3

    Figure 3. Kinome selectivity depiction for compound 2. Inhibition data (%) are shown for a compound test concentration of 1 μM. PI3K isoforms are indicated as α, β, γ, δ. Data are in Supporting Information, Table T1.

    Figure 4

    Figure 4. Colon and gastric tumor cell line responses for ATR inhibitors 1, 2, 3 compared with NVPBEZ-235 (labeled pPI3/mTORi) (6) (mTOR, PI3K, ATR, ATM, DNA-PK), AZD8186 (50) (labeled PI3Kβ+δ), and AZD8835 (51) (labeled PI3Kα+δ). Data shown are normalized as pGI50 minus mean pGI50 across the panel to correct for the influence of absolute potency. Hierarchical clustering of profiles is shown on the right.

    Figure 5

    Figure 5. Exposure of ATR inhibitors 1, 2, 15, 21, and 35 is correlated to tumor growth inhibition (TGI). The observed plasma concentrations following a single dose of each compound were multiplied by the compound specific in vitro measured free fraction and divided by in vitro GI50 to give fold free concentration above GI50. The time above in vitro LoVo GI50 is plotted against LoVo xenograft tumor growth inhibition in vivo. A logarithmic trendline (Log.(All)) best-fit curve is shown for all compounds.

    Figure 6

    Figure 6. In vivo tumor growth inhibition (TGI) for compound 2. Top graph: Female nude mice bearing established human LoVo (MRE11A mutant/ATM deficient) colorectal adenocarcinoma xenografts were dosed orally with either vehicle (◆) or 2 at 10 mg/kg once daily (×, day 22 TGI = 7%, p = ns), 25 mg/kg once daily (■, day 22 TGI = 38%, p < 0.049), 50 mg/kg once daily (△, day 22 TGI = 89%, p < 0.0005). Bottom graph: Female nude mice bearing established HT-29 (MRE11A wild type/ATM-proficient) colorectal adenocarcinoma xenografts were dosed orally with either vehicle (◆) or 2 at 25 mg/kg twice daily (●, day 27 TGI = 5%, p = ns), 50 mg/kg once daily (△, day 27 TGI = 10%, p = ns) or 75 mg/kg once daily (□, day 27 TGI = 30%, p < 0.005); ns = not significant.

    Figure 7

    Figure 7. Compound 2 γH2AX DNA-damage biomarker pharmacodynamics in established LoVo tumor xenografts in female nude mice. Mice were dosed with either vehicle or 2 at 10 mg/kg, 25 mg/kg, 50 mg/kg, or 75 mg/kg once daily for 4 consecutive days before tissue sampling at 8 or 24 h after the fourth dose (day 4). Data are presented as average % γH2AX positive tissue per total tumor area counted ± standard deviation (N = 4 independent mouse/tumors per point).

  • References

    ARTICLE SECTIONS
    Jump To

    This article references 63 other publications.

    1. 1
      O’Connor, M. J. Targeting the DNA damage response in cancer. Mol. Cell 2015, 60, 547560,  DOI: 10.1016/j.molcel.2015.10.040
    2. 2
      Jackson, S. P.; Helleday, T. DNA Repair. Drugging DNA repair. Science 2016, 352, 11781179,  DOI: 10.1126/science.aab0958
    3. 3
      Yazinski, S. A.; Zou, L. Functions, regulation, and therapeutic implications of the ATR checkpoint pathway. Annu. Rev. Genet. 2016, 50, 155173,  DOI: 10.1146/annurev-genet-121415-121658
    4. 4
      Cimprich, K. A.; Cortez, D. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 2008, 9, 616627,  DOI: 10.1038/nrm2450
    5. 5
      Macheret, M.; Halazonetis, T. D. DNA replication stress as a hallmark of cancer. Annu. Rev. Pathol.: Mech. Dis. 2015, 10, 425448,  DOI: 10.1146/annurev-pathol-012414-040424
    6. 6
      Foote, K. M.; Lau, A.; Nissink, J. W. M. Drugging ATR: progress in the development of specific inhibitors for the treatment of cancer. Future Med. Chem. 2015, 7, 873891,  DOI: 10.4155/fmc.15.33
    7. 7
      Weber, A. M.; Ryan, A. J. ATM and ATR as therapeutic targets in cancer. Pharmacol. Ther. 2015, 149, 124138,  DOI: 10.1016/j.pharmthera.2014.12.001
    8. 8
      Sundar, R.; Brown, J.; Ingles Russo, A.; Yap, T. A. Targeting ATR in cancer medicine. Curr. Probl. Cancer 2017, 41, 302315,  DOI: 10.1016/j.currproblcancer.2017.05.002
    9. 9
      Rundle, S.; Bradbury, A.; Drew, Y.; Curtin, N. J. Targeting the ATR-CHK1 axis in cancer therapy. Cancers 2017, 9, E41,  DOI: 10.3390/cancers9050041
    10. 10
      Kwok, M.; Davies, N.; Agathanggelou, A.; Smith, E.; Oldreive, C.; Petermann, E.; Stewart, G.; Brown, J.; Lau, A.; Pratt, G.; Parry, H.; Taylor, M.; Moss, P.; Hillmen, P.; Stankovic, T. ATR inhibition induces synthetic lethality and overcomes chemoresistance in TP53- or ATM-defective chronic lymphocytic leukemia cells. Blood 2016, 127, 582595,  DOI: 10.1182/blood-2015-05-644872
    11. 11
      Min, A.; Im, S. A.; Jang, H.; Kim, S.; Lee, M.; Kim, D. K.; Yang, Y.; Kim, H. J.; Lee, K. H.; Kim, J. W.; Kim, T. Y.; Oh, D. Y.; Brown, J.; Lau, A.; O’Connor, M. J.; Bang, Y. J. AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells. Mol. Cancer Ther. 2017, 16, 566577,  DOI: 10.1158/1535-7163.MCT-16-0378
    12. 12
      Vendetti, F. P.; Lau, A.; Schamus, S.; Conrads, T. P.; O’Connor, M. J.; Bakkenist, C. J. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget 2015, 6, 4428944305,  DOI: 10.18632/oncotarget.6247
    13. 13
      Dillon, M. T.; Barker, H. E.; Pedersen, M.; Hafsi, H.; Bhide, S. A.; Newbold, K. L.; Nutting, C. M.; McLaughlin, M.; Harrington, K. J. Radiosensitization by the ATR inhibitor AZD6738 through generation of acentric micronuclei. Mol. Cancer Ther. 2017, 16, 2534,  DOI: 10.1158/1535-7163.MCT-16-0239
    14. 14
      Dunne, V.; Ghita, M.; Small, D. M.; Coffey, C. B. M.; Weldon, S.; Taggart, C. C.; Osman, S. O.; McGarry, C. K.; Prise, K. M.; Hanna, G. G.; Butterworth, K. T. Inhibition of ataxia telangiectasia related-3 (ATR) improves therapeutic index in preclinical models of non-small cell lung cancer (NSCLC) radiotherapy. Radiother. Oncol. 2017, 124, 475481,  DOI: 10.1016/j.radonc.2017.06.025
    15. 15
      Kim, H.; George, E.; Ragland, R.; Rafail, S.; Zhang, R.; Krepler, C.; Morgan, M.; Herlyn, M.; Brown, E.; Simpkins, F. Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models. Clin. Cancer Res. 2017, 23, 30973108,  DOI: 10.1158/1078-0432.CCR-16-2273
    16. 16
      Foote, K. M.; Blades, K.; Cronin, A.; Fillery, S.; Guichard, S. S.; Hassall, L.; Hickson, I.; Jacq, X.; Jewsbury, P. J.; McGuire, T. M.; Nissink, J. W.; Odedra, R.; Page, K.; Perkins, P.; Suleman, A.; Tam, K.; Thommes, P.; Broadhurst, R.; Wood, C. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-y l}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J. Med. Chem. 2013, 56, 21252138,  DOI: 10.1021/jm301859s
    17. 17
      Menezes, D. L.; Holt, J.; Tang, Y.; Feng, J.; Barsanti, P.; Pan, Y.; Ghoddusi, M.; Zhang, W.; Thomas, G.; Holash, J.; Lees, E.; Taricani, L. A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function. Mol. Cancer Res. 2015, 13, 120129,  DOI: 10.1158/1541-7786.MCR-14-0240
    18. 18
      Wengner, A.; Siemeister, G.; Luecking, U.; Lefranc, J.; Lienau, P.; Deeg, G.; Lagkadinou, E.; Liu, L.; Golfier, S.; Schatz, C.; Scholz, A.; von Nussbaum, F.; Brands, M.; Mumberg, D.; Ziegelbauer, K. ATR Inhibitor BAY 1895344 Shows Potent Anti-Tumor Efficacy in Monotherapy and Strong Combination Potential with the Targeted Alpha Therapy Radium-223 Dichloride in Preclinical Tumor Models. Proceedings, AACR Annual Meeting, Washington, DC, 2017; AACR: Philadelphia, PA, 2017.
    19. 19
      Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-catalyzed cross-coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters. J. Org. Chem. 1995, 60, 75087510,  DOI: 10.1021/jo00128a024
    20. 20
      Goundry, W. R. F.; Adams, B.; Benson, H.; Demeritt, J.; McKown, S.; Mulholland, K.; Robertson, A.; Siedlecki, P.; Tomlin, P.; Vare, K. Development and scale-up of a biocatalytic process to form a chiral sulfoxide. Org. Process Res. Dev. 2017, 21, 107113,  DOI: 10.1021/acs.oprd.6b00391
    21. 21
      Okamura, H.; Bolm, C. Rhodium-catalyzed imination of sulfoxides and sulfides: efficient preparation of N-unsubstituted sulfoximines and sulfilimines. Org. Lett. 2004, 6, 13051307,  DOI: 10.1021/ol049715n
    22. 22
      Dresser, G. K.; Spence, J. D.; Bailey, D. G. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin. Pharmacokinet. 2000, 38, 4157,  DOI: 10.2165/00003088-200038010-00003
    23. 23
      Kalgutkar, A. S.; Obach, R. S.; Maurer, T. S. Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Curr. Drug Metab. 2007, 8, 407447,  DOI: 10.2174/138920007780866807
    24. 24
      Hollenberg, P. F.; Kent, U. M.; Bumpus, N. N. Mechanism-based inactivation of human cytochromes p450s: experimental characterization, reactive intermediates, and clinical implications. Chem. Res. Toxicol. 2008, 21, 189205,  DOI: 10.1021/tx7002504
    25. 25
      Curatolo, W. Physical chemical properties of oral drug candidates in the discovery and exploratory development settings. Pharm. Sci. Technol. Today 1998, 1, 387393,  DOI: 10.1016/S1461-5347(98)00097-2
    26. 26
      Kenny, J. R.; Mukadam, S.; Zhang, C.; Tay, S.; Collins, C.; Galetin, A.; Khojasteh, S. C. Drug-drug interaction potential of marketed oncology drugs: in vitro assessment of time-dependent cytochrome P450 inhibition, reactive metabolite formation and drug-drug interaction prediction. Pharm. Res. 2012, 29, 19601976,  DOI: 10.1007/s11095-012-0724-6
    27. 27
      Stepan, A. F.; Walker, D. P.; Bauman, J.; Price, D. A.; Baillie, T. A.; Kalgutkar, A. S.; Aleo, M. D. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem. Res. Toxicol. 2011, 24, 13451410,  DOI: 10.1021/tx200168d
    28. 28
      Cytochrome P450 3A4 and 3A5 Known Drug Interaction Chart. http://www.mayomedicallaboratories.com/it-mmfiles/Cytochrome_P450_3A4_and_3A5_Known_Drug_Interaction_Chart.pdf (accessed June 5, 2018).
    29. 29
      Overton, M.; Hickman, J. A.; Threadgill, M. D.; Vaughan, K.; Gescher, A. The generation of potentially toxic, reactive iminium ions from the oxidative metabolism of xenobiotic N-alkyl compounds. Biochem. Pharmacol. 1985, 34, 20552061,  DOI: 10.1016/0006-2952(85)90394-6
    30. 30
      Masic, L. P. Role of cyclic tertiary amine bioactivation to reactive iminium species: structure toxicity relationship. Curr. Drug Metab. 2011, 12, 3550,  DOI: 10.2174/138920011794520044
    31. 31
      Bolleddula, J.; DeMent, K.; Driscoll, J. P.; Worboys, P.; Brassil, P. J.; Bourdet, D. L. Biotransformation and bioactivation reactions of alicyclic amines in drug molecules. Drug Metab. Rev. 2014, 46, 379419,  DOI: 10.3109/03602532.2014.924962
    32. 32
      Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O’Donnell, J. P. Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem. Res. Toxicol. 2002, 15, 269299,  DOI: 10.1021/tx015574b
    33. 33
      Inoue, K.; Fukuda, K.; Yoshimura, T.; Kusano, K. Comparison of the reactivity of trapping reagents toward electrophiles: cysteine derivatives can be bifunctional trapping reagents. Chem. Res. Toxicol. 2015, 28, 15461555,  DOI: 10.1021/acs.chemrestox.5b00129
    34. 34
      Atkinson, A.; Kenny, J. R.; Grime, K. Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis. Drug. Metab. Dispos. 2005, 33, 16371647,  DOI: 10.1124/dmd.105.005579
    35. 35
      Kaplan, J.; Verheijen, J. C.; Brooijmans, N.; Toral-Barza, L.; Hollander, I.; Yu, K.; Zask, A. Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Bioorg. Med. Chem. Lett. 2010, 20, 640643,  DOI: 10.1016/j.bmcl.2009.11.050
    36. 36
      Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.; Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Yu, K. Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors. J. Med. Chem. 2009, 52, 79427945,  DOI: 10.1021/jm901415x
    37. 37
      Safina, B. S.; Baker, S.; Baumgardner, M.; Blaney, P. M.; Chan, B. K.; Chen, Y. H.; Cartwright, M. W.; Castanedo, G.; Chabot, C.; Cheguillaume, A. J.; Goldsmith, P.; Goldstein, D. M.; Goyal, B.; Hancox, T.; Handa, R. K.; Iyer, P. S.; Kaur, J.; Kondru, R.; Kenny, J. R.; Krintel, S. L.; Li, J.; Lesnick, J.; Lucas, M. C.; Lewis, C.; Mukadam, S.; Murray, J.; Nadin, A. J.; Nonomiya, J.; Padilla, F.; Palmer, W. S.; Pang, J.; Pegg, N.; Price, S.; Reif, K.; Salphati, L.; Savy, P. A.; Seward, E. M.; Shuttleworth, S.; Sohal, S.; Sweeney, Z. K.; Tay, S.; Tivitmahaisoon, P.; Waszkowycz, B.; Wei, B.; Yue, Q.; Zhang, C.; Sutherlin, D. P. Discovery of novel PI3-kinase delta specific inhibitors for the treatment of rheumatoid arthritis: taming CYP3A4 time-dependent inhibition. J. Med. Chem. 2012, 55, 58875900,  DOI: 10.1021/jm3003747
    38. 38
      Pennington, L. D.; Moustakas, D. T. The necessary nitrogen atom: a versatile high-impact design element for multiparameter optimization. J. Med. Chem. 2017, 60, 35523579,  DOI: 10.1021/acs.jmedchem.6b01807
    39. 39
      Lu, Y.; Knapp, M.; Crawford, K.; Warne, R.; Elling, R.; Yan, K.; Doyle, M.; Pardee, G.; Zhang, L.; Ma, S.; Mamo, M.; Ornelas, E.; Pan, Y.; Bussiere, D.; Jansen, J.; Zaror, I.; Lai, A.; Barsanti, P.; Sim, J. Rationally designed PI3Kalpha mutants to mimic ATR and their use to understand binding specificity of ATR inhibitors. J. Mol. Biol. 2017, 429, 16841704,  DOI: 10.1016/j.jmb.2017.04.006
    40. 40
      Rao, Q.; Liu, M.; Tian, Y.; Wu, Z.; Hao, Y.; Song, L.; Qin, Z.; Ding, C.; Wang, H. W.; Wang, J.; Xu, Y. Cryo-EM structure of human ATR-ATRIP complex. Cell Res. 2018, 28, 143156,  DOI: 10.1038/cr.2017.158
    41. 41
      Adler, T. K.; Albert, A. Diazaindenes (“azaindoles”). Part I. Ionization constants and spectra. J. Chem. Soc. 1960, 0, 17941797,  DOI: 10.1039/JR9600001794
    42. 42
      Kawashima, S.; Matsuno, T.; Yaguchi, S.; Sasahara, H.; Watanabe, T. Heterocyclic Compound and Antitumor Agent Containing the Same as Active Ingredient. WO2002088112, 2002.
    43. 43
      Scott, J. S.; Birch, A. M.; Brocklehurst, K. J.; Broo, A.; Brown, H. S.; Butlin, R. J.; Clarke, D. S.; Davidsson, O.; Ertan, A.; Goldberg, K.; Groombridge, S. D.; Hudson, J. A.; Laber, D.; Leach, A. G.; Macfaul, P. A.; McKerrecher, D.; Pickup, A.; Schofield, P.; Svensson, P. H.; Sorme, P.; Teague, J. Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation. J. Med. Chem. 2012, 55, 53615379,  DOI: 10.1021/jm300310c
    44. 44
      Lucking, U. Sulfoximines: a neglected opportunity in medicinal chemistry. Angew. Chem., Int. Ed. 2013, 52, 93999408,  DOI: 10.1002/anie.201302209
    45. 45
      Sirvent, J. A.; Lucking, U. Novel pieces for the emerging picture of sulfoximines in drug discovery: synthesis and evaluation of sulfoximine analogues of marketed drugs and advanced clinical candidates. ChemMedChem 2017, 12, 487501,  DOI: 10.1002/cmdc.201700044
    46. 46
      Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Sulfoximines from a medicinal chemist’s perspective: physicochemical and in vitro parameters relevant for drug discovery. Eur. J. Med. Chem. 2017, 126, 225245,  DOI: 10.1016/j.ejmech.2016.09.091
    47. 47
      Redfern, W. S.; Carlsson, L.; Davis, A. S.; Lynch, W. G.; MacKenzie, I.; Palethorpe, S.; Siegl, P. K.; Strang, I.; Sullivan, A. T.; Wallis, R.; Camm, A. J.; Hammond, T. G. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 2003, 58, 3245,  DOI: 10.1016/S0008-6363(02)00846-5
    48. 48
      Fokas, E.; Prevo, R.; Pollard, J. R.; Reaper, P. M.; Charlton, P. A.; Cornelissen, B.; Vallis, K. A.; Hammond, E. M.; Olcina, M. M.; Gillies McKenna, W.; Muschel, R. J.; Brunner, T. B. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012, 3, e441,  DOI: 10.1038/cddis.2012.181
    49. 49
      Jacq, X.; Smith, L.; Brown, E.; Hughes, A.; Odedra, R.; Heathcote, D.; Barnes, J.; Powell, S.; Maguire, S.; Pearson, V.; Boros, J.; Caie, P.; Thommes, P. A.; Nissink, W.; Foote, K.; Jewsbury, P. J.; Guichard, S. M. AZ20, a novel potent and selective inhibitor of ATR kinase with in vivo antitumour activity. Cancer Res. 2012, 72 (8, Suppl.), 1823,  DOI: 10.1158/1538-7445.AM2012-1823
    50. 50
      Barlaam, B.; Cosulich, S.; Degorce, S.; Fitzek, M.; Green, S.; Hancox, U.; Lambert-van der Brempt, C.; Lohmann, J. J.; Maudet, M.; Morgentin, R.; Pasquet, M. J.; Peru, A.; Ple, P.; Saleh, T.; Vautier, M.; Walker, M.; Ward, L.; Warin, N. Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chrom ene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kbeta and PI3Kdelta for the treatment of PTEN-deficient cancers. J. Med. Chem. 2015, 58, 943962,  DOI: 10.1021/jm501629p
    51. 51
      Barlaam, B.; Cosulich, S.; Delouvrie, B.; Ellston, R.; Fitzek, M.; Germain, H.; Green, S.; Hancox, U.; Harris, C. S.; Hudson, K.; Lambert-van der Brempt, C.; Lebraud, H.; Magnien, F.; Lamorlette, M.; Le Griffon, A.; Morgentin, R.; Ouvry, G.; Page, K.; Pasquet, G.; Polanska, U.; Ruston, L.; Saleh, T.; Vautier, M.; Ward, L. Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4 -triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kalpha and PI3Kdelta for the treatment of cancers. Bioorg. Med. Chem. Lett. 2015, 25, 51555162,  DOI: 10.1016/j.bmcl.2015.10.002
    52. 52
      Bonner, W. M.; Redon, C. E.; Dickey, J. S.; Nakamura, A. J.; Sedelnikova, O. A.; Solier, S.; Pommier, Y. GammaH2AX and cancer. Nat. Rev. Cancer 2008, 8, 957967,  DOI: 10.1038/nrc2523
    53. 53
      Chen, T.; Middleton, F. K.; Falcon, S.; Reaper, P. M.; Pollard, J. R.; Curtin, N. J. Development of pharmacodynamic biomarkers for ATR inhibitors. Mol. Oncol. 2015, 9, 463472,  DOI: 10.1016/j.molonc.2014.09.012
    54. 54
      Nestorov, I. A.; Aarons, L. J.; Arundel, P. A.; Rowland, M. Lumping of whole-body physiologically based pharmacokinetic models. J. Pharmacokinet. Biopharm. 1998, 26, 2146
    55. 55
      Luttringer, O.; Theil, F. P.; Poulin, P.; Schmitt-Hoffmann, A. H.; Guentert, T. W.; Lave, T. Physiologically based pharmacokinetic (PBPK) modeling of disposition of epiroprim in humans. J. Pharm. Sci. 2003, 92, 19902007,  DOI: 10.1002/jps.10461
    56. 56
      Sjögren, E.; Westergren, J.; Grant, I.; Hanisch, G.; Lindfors, L.; Lennernas, H.; Abrahamsson, B.; Tannergren, C. In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. Eur. J. Pharm. Sci. 2013, 49, 679698,  DOI: 10.1016/j.ejps.2013.05.019
    57. 57
      Ding, X.; Rose, J. P.; Van Gelder, J. Developability assessment of clinical drug products with maximum absorbable doses. Int. J. Pharm. 2012, 427, 260269,  DOI: 10.1016/j.ijpharm.2012.02.003
    58. 58
      McGinnity, D. F.; Collington, J.; Austin, R. P.; Riley, R. J. Evaluation of human pharmacokinetics, therapeutic dose and exposure predictions using marketed oral drugs. Curr. Drug Metab. 2007, 8, 463479,  DOI: 10.2174/138920007780866799
    59. 59
      Sohlenius-Sternbeck, A. K.; Jones, C.; Ferguson, D.; Middleton, B. J.; Projean, D.; Floby, E.; Bylund, J.; Afzelius, L. Practical use of the regression offset approach for the prediction of in vivo intrinsic clearance from hepatocytes. Xenobiotica 2012, 42, 841853,  DOI: 10.3109/00498254.2012.669080
    60. 60
      Yap, T. A.; Krebs, M. G.; Postel-Vinay, S.; Bang, Y. J.; El-Khoueiry, A.; Abida, W.; Harrington, K.; Sundar, R.; Carter, L.; Castanon-Alvarez, E.; Im, S. A.; Berges, A.; Khan, M.; Stephens, C.; Ross, G.; Soria, J. C. Phase I modular study of AZD6738, a novel oral, potent and selective ataxia telangiectasia Rad3-related (ATR) inhibitor in combination (combo) with carboplatin, olaparib or durvalumab in patients (pts) with advanced cancers. Eur. J. Cancer 2016, 69, S2,  DOI: 10.1016/S0959-8049(16)32607-7
    61. 61
      Krebs, M. G.; Lopez, J.; El-Khoueiry, A.; Bang, Y.-J.; Postel-Vinay, S.; Abida, W.; Carter, L.; Xu, W.; Im, S.-A.; Pierce, A.; Frewer, P.; Berges, A.; Cheung, S. Y. A.; Stephens, C.; Felicetti, B.; Dean, E.; Hollingsworth, S. J. Phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Proceedings of the American Association for Cancer Research Annual Meeting 2018, Chicago, IL, Apr 14–18, 2018; AACR: Philadelphia, PA, 2018;
      Cancer Res 2018, 78 (13, Suppl.), CT026, DOI: 10.1158/1538-7445.AM2018-CT026
    62. 62
      Berges, A.; Cheung, S. Y. A.; Pierce, A.; Dean, E.; Felicetti, B.; Standifer, N.; Smith, S.; Yates, J.; Lau, A.; Stephens, C.; Krebs, M. G.; Harrington, K.; Hollingsworth, S. J. PK-Biomarker-Safety modelling aids choice of recommended Phase II dose and schedule for AZD6738 (ATR inhibitor). Proceedings of the American Association for Cancer Research Annual Meeting 2018, Chicago, IL, Apr 14–18, 2018; AACR: Philadelphia, PA, 2018;
      Cancer Res. 2018, 78 (13, Suppl.), CT118,  DOI: 10.1158/1538-7445.AM2018-CT118
    63. 63
      Lloyd, R.; Falenta, K.; Wijnhoven, P. W.; Chabbert, C.; Stott, J.; Yates, J.; Lau, A. Y.; Young, L. A.; Hollingsworth, S. J. The PARP inhibitor olaparib is synergistic with the ATR inhibitor AZD6738 in ATM deficient cancer cells. Proceedings of the American Association for Cancer Research Annual Meeting 2018, Chicago, IL, Apr 14–18, 2018; AACR: Philadelphia, PA, 2018;
      Cancer Res. 2018, 78 (13, Suppl.), 337, DOI: 10.1158/1538-7445.AM2018-337
  • Supporting Information

    Supporting Information

    ARTICLE SECTIONS
    Jump To

    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b01187.

    • Figure S1 showing kinome tree graphs for 3, 21, 15; Table T1 listing kinase inhibition data for 2; Table T2 listing ATR activity data for 37, 38; Scheme S1 showing synthetic route to 37 and 38; crystallization methods for compound 2; experimental details and data for compounds 532, 3438, 4045, 5069, R/S-73, 7779; crystal formation method of R-72; Figure S2 showing X-ray structure of R-72; aqueous solubility, log D7.4 methods (PDF)

    • Molecular formula strings (CSV)


    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.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect