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Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR

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Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
*Phone: (650) 467-3214. Fax: (650) 225-2061. E-mail: [email protected]
Cite this: ACS Med. Chem. Lett. 2016, 7, 4, 351–356
Publication Date (Web):February 16, 2016
https://doi.org/10.1021/acsmedchemlett.6b00005

Copyright © 2016 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood–brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.

Owing to an associated poor prognosis and limited treatment options, glioblastoma multiforme (GBM) represents a significant unmet medical need. (1) In this particular disease, aberrant PI3K signaling is associated with >80% of cases. (2) While numerous PI3K inhibitors have advanced to clinical study, (3) to treat GBM effectively it is anticipated that the inhibitor would need to freely cross the blood–brain barrier (BBB). To this end, we have previously reported on our initial efforts to identify BBB penetrating PI3K inhibitors. (4) In those efforts molecules 1 and 2 (Table 1) were identified, which freely crossed the BBB and demonstrated a PD effect in normal mouse brain tissue as well as efficacy in intracranial mouse tumor models of GBM. Despite the evident free brain penetration of 1 and 2, they were not selected for clinical development due to poor projected clearance in humans (based on both human liver microsomal stability, Table 1, and allometric scaling, data not shown). We, therefore, extended our efforts to identify potent, BBB penetrating inhibitors of PI3K with more desirable metabolic stability that would be suitable for clinical study.

We continued our efforts to identify brain penetrating inhibitors of PI3K by attempting to identify analogues of thienopyrimidines 1 and 2 that attained an acceptable combination of low transporter mediated efflux, good potency, and low projected human clearance. In our attempts, we identified potent molecules that achieved good metabolic stability in human liver microsomes and many potent molecules that had low efflux ratios in MDR1 (gene coding for P-glycloprotein, P-gp) and breast cancer resistance protein (Bcrp) transfected MDCK cell permeability assays (data not shown). The combination of good human metabolic stability and low efflux ratios in this thienopyrimidine series of analogues, however, remained elusive. As a result we sought an alternative series of molecules that might allow for the desired combination of properties.

Prior to our efforts to identify BBB penetrating PI3K inhibitors, we had identified clinical inhibitors of PI3K that were suited for the treatment of peripheral disease. In our studies leading to the discovery of GDC-0980 (3, Table 1), (5) a pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor from the same thienopyrimidine scaffold as 1 and 2, we had also studied a related purine scaffold (e.g., 4, Table 1). Compounds within this purine series of PI3K inhibitors that had good human microsomal stability were readily identified. As an example, while it did not advance to clinical development, compound 4 was identified as a pan-PI3K inhibitor on a purine scaffold that had appealing projected human clearance based on liver microsomal stability (Table 1).

Table 1. MDR1 and Bcrp1 Transfected MDCK Cell Permeability Efflux Ratios and Human Liver Microsomal Stability for Previously Identified PI3K Inhibitors 14
CompoundPI3Kα KiappmTOR KiappPC3 Proliferation EC50B–A/A–B (MDR1)B–A/A–B (Bcrpl)[brain]u/[plasma]uHLM Clhep (mL/min/kg)
11 nM10 nM0.17 μM0.93.70.4a10.4
22 nM9 nM0.13 μM1.81.30.4b9.8
35 nM17 nM0.31 μM197<0.05c3.1
43 nM950 nM0.33 μM4271 2.8
a

Determined 6 h after administration of 25 mg/kg orally to female CD-1 mice as an MCT suspension.

b

Determined 6 h after administration of 50 mg/kg orally to female CD-1 mice as an MCT suspension.

c

Determined 1 h after administration of 20 mg/kg to female CD-1 mice as an MCT suspension.

With our knowledge that desirable metabolic stability was attainable on a purine scaffold, we resolved to evaluate purine-based inhibitors for their potential to achieve the desired balance of potency, metabolic stability, and low transporter mediated efflux. The previous purine PI3K inhibitors that we had made, such as 4, were not designed to have low P-gp and Bcrp mediated efflux. Indeed, compound 4 was not expected to be freely BBB penetrating given the high number of hydrogen bond donors in the molecule. In fact, compound 4 is a significant substrate of both P-gp and Bcrp as determined by the efflux ratios in cell permeability assays (Table 1). It remained to be seen whether or not we could realize purine PI3K inhibitors that were capable of avoiding transport by P-gp and Bcrp while also maintaining good human metabolic stability.

At first we were concerned that the additional polarity of a purine scaffold, relative to a thienopyrimidine, might render such molecules more likely to be transporter substrates. To evaluate the feasibility of a purine core for brain penetration, we first studied compound 5 (Table 2). Despite a topological polar surface area (TPSA) of 107 Å2, 5 has a low efflux ratio in a P-gp transfected MDCK cell permeability assay. Additionally, compound 5 showed encouraging human microsomal stability. Unfortunately, this analogue lacked potency in a PC3 cell proliferation assay. Nevertheless, we were encouraged that the combination of low efflux and good human microsomal stability that was unattainable in the thienopyrimidine series of molecules could be obtained on a purine-based PI3K inhibitor. We were then pleased to find that substitution at R1 with either ethyl (6) or cyclobutyl (7) groups improved the cellular potency and maintained low efflux ratios (Table 2). However, the ethyl and cyclobutyl substitutions each led to reduced human liver microsomal stability. Compound 8 was even more potent than the previous purine analogues and had excellent human liver microsomal stability (Table 2). The introduction of a new hydrogen bond donor relative to compounds 57, however, led to very high efflux ratios for 8. This result was consistent with our experience with thienopyrimidine PI3K inhibitors and led us to synthesize compound 9, the methyl ether analogue of 8 and a direct analogue of thienopyrimidine 2. Compound 9 retained the excellent cellular potency of 8 and, as we had suspected, the conversion of the tertiary alcohol of 8 to the methyl ether of 9 ablated P-gp and Bcrp mediated efflux. While the human liver microsomal stability of 9 was moderate, we sought to further improve upon this result.

Table 2. Cellular Potency, TPSA, Efflux Ratios, and Human Metabolic Stability for Select Purine PI3K Inhibitors

The excellent metabolic stability of compound 4 had initially incited our investigation of whether we could realize brain penetrating purine PI3K inhibitors. Its excellent potency and metabolic stability were desirable, but the efflux ratios suggested the molecule would not freely penetrate the BBB (Table 2). We, therefore, sought to eliminate the two hydrogen bond donors of the alcohols in compound 4 in an effort to reduce transporter mediated efflux. Rather than alkylation of the alcohols of 4, we investigated the effective result of ring closing condensation.

The first cyclized analogue of 4 using this approach, compound 15 (Table 3), was found to have excellent human metabolic stability and low efflux ratios but modest cellular potency (Table 3). We previously found that analogues without R1 substitution were more potent inhibitors of mTOR and generally had better cellular potency in cell lines whose proliferation were driven by aberrant PI3K signaling. (6) Compound 16, where R1 is H, achieved an excellent balance of cellular potency, metabolic stability, and lack of efflux (Table 3). Additionally, compound 16 was found to be highly selective against a panel of 229 kinases where it inhibited none by >50% (1 μM 16, Supporting Information). Furthermore, 16 maintains inhibition of each of the Class I PI3K isoforms (Supporting Information) but with more potent inhibition of mTOR. Compound 16 was also tested in five different GBM cell lines and was found to have antiproliferative EC50s ranging from 0.3 to 1.1 μM. (7)

Scheme 1

Scheme 1. Synthetic Route to Obtain Tricyclic Purine-Based Brain Penetrant PI3K Inhibitor 16

The synthesis of 16 (Scheme 1) began with lithiation of purine 10 (8) followed by alkylation with acetone to provide tertiary alcohol 11. The THP group was next deprotected to provide 12. Subsequent alkylation with 1,2-dibromoethane afforded the annulated product 13. Finally, Suzuki coupling of 13 with boronate ester 14 afforded the final compound 16.

Table 3. Potency, Efflux Ratios, and Human Metabolic Stability of Tricyclic Purine-Based PI3K Inhibitors 15 and 16
CompoundR1PI3Kα KiappmTOR KiappPC3 Proliferation EC50B–A/A–B (MDR1)B–A/A–B (Bcrpl)HLM Clhep (mL/m in/kg)HH Clhep (mL/min/kg)
15Me2 nM1.2 μM2.0 μM1.73.33.11.2
16H2 nM0.07 μM0.4 μM0.81.65.01.0

The appealing in vitro properties of 16 described in Table 3 led us to evaluate it in in vivo pharmacokinetic studies. Table 4 includes the microsomal stability of 16 as well as key in vivo pharmacokinetic parameters in rodents. The correlation between in vivo clearance and predicted clearance based on microsomal stability gave us greater confidence that human clearance would be low as predicted in a human metabolic stability assays (Table 3).

Table 4. Preclinical Species Hepatocyte Stability and in Vivo Pharmacokinetic Data for 16
  IV (1 mg/kg)bPOc
Speciesliver microsomes Clhep (mL/min/kg)ain vivo Cl (mL/min/kg)Vss (L/kg)Dose (mg/kg)AUC (μM·h)F%PPB%
Mouse19171.725477578
Rat14283.258.37771
a

Hepatic clearance was predicted from liver microsomes incubations using the “in vitro t1/2 method.” (9)

b

Male Sprague–Dawley rats or female CD-1 mice were dosed intravenously with 1 mg/kg of 16 prepared in 60% PEG400/10% ethanol.

c

Compound 16 was administered PO at the indicated dose in 0.5% methylcellulose with 0.2% Tween 80 (MCT).

To verify that 16 was indeed capable of penetrating the BBB, we determined the brain-to-plasma ratio in rats. After a 15 mg/kg dose of 16, the total brain-to-plasma ratio was 1.9–3.3. While we did not determine brain binding for rats and therefore cannot report Bu/Pu, we determined the concentration of 16 in cerebral spinal fluid (CSF). The CSF concentration is sometimes employed as a surrogate for unbound brain concentration. (10) We found that the CSF-to-free plasma concentration ratio in rats was 0.7–1.0, indicating that 16 effectively penetrates the BBB (Figure 1). In addition to demonstrating that 16 is capable of crossing the BBB in rats, we determined the unbound brain-to-unbound plasma concentration (Bu/Pu) ratio in female CD-1 mice. The Bu/Pu ratio of 0.4, at both 1 and 6 h post 25 mg/kg oral dose of 16, demonstrates the molecule is capable of substantial free brain penetration (Figure 1).

Figure 1

Figure 1. CNS penetration of 16 in rat and mouse. [Brain]/[Plasma] ratios determined after oral dose of 16 to female CD-1 mice or male Sprague–Dawley rats as an MCT suspension. *[Brain]u and [Plasma]u refer to the unbound concentration measured in the brain and plasma, respectively. **[CSF] refers to the concentration measured in the cerebral spinal fluid. aDetermined to be identical at both 1 and 6 h after administration of 25 mg/kg 16 to female CD-1 mice. The [Brain]/[Plasma] ratios are the mean values from 3 animals per time point. bDetermined after administration of 15 mg/kg 16 to male Sprague–Dawley rats. [Brain]/[Plasma] determined for 1 animal at each of 0.25 and 2 h and 3 at 8 h. Data reported are the range across the three time points (average of the 3 animals at 8 h). c[CSF] determined for 1 animal at each of 0.25 and 2 h and 3 at 8 h. Data reported are the range across the three time points (average of the 3 animals at 8 h).

To further verify that 16 was indeed capable of penetrating the BBB to engage its target where intended, we evaluated the effect of 16 on pAKT in normal brain tissue. After a 25 mg/kg dose of 16 administered orally, pAKT in normal mouse brain tissue was significantly inhibited at 1 and 6 h postdose (Figure 2). The potent inhibition of pAKT at both time points in this study demonstrates that 16 inhibits its target behind a fully intact BBB.

Figure 2

Figure 2. Inhibition of p-AKT by 16 in normal mouse brain tissue along with corresponding brain and unbound brain concentrations. *Significantly different from untreated control. p < 0.05, t test. [Brain] determined after 25 mg/kg oral dose of 16 female CD-1 mice as an MCT suspension. [Brain]u refers to the unbound concentration measured in the brain. Data are reported as mean values ± SD from 3 animals per time point.

In addition to the pharmacodynamic effect in normal brain tissue, 16 was studied in a subcutaneous U87 tumor xenograft model of glioblastoma in mice. (11) In this study, 16 achieved significant and dose-dependent tumor growth inhibition (Figure 3). Tumor growth inhibition was first observed at a 2.2 mg/kg dose level. Higher doses led to greater tumor growth inhibition, including tumor regressions at the 17.9 mg/kg dose level. Each of these doses was well tolerated for the duration of the study.

Figure 3

Figure 3. In vivo efficacy of 16 versus U87 MG/M human glioblastoma xenografts. Female NCr nude mice bearing subcutaneous tumors were administered escalating doses of 16 orally as a suspension in vehicle (0.5% methylcellulose/0.2% Tween-80) or vehicle once daily (QD) for 23 days. Changes in tumor volumes over time by dose for each compound are depicted as cubic spline fits generated via Linear Mixed Effects analysis of log-transformed volumes.

Consistent with the efficacy observed in the U87 xenograft tumor study, at similar dose levels compound 16 was found to have a significant PD effect in the U87 tumors. Dose- and concentration-dependent inhibition of pAKT was observed at both 1 and 4 h postdose, indicating that the tumor growth inhibition is the result of on-target inhibition (Figure 4).

The U87 subcutaneous tumor model can be considered a surrogate for the intracranial U87 model because the intracranial model has a compromised blood–brain barrier following engraftment. (12) We previously studied a different BBB penetrating PI3K/mTOR inhibitor in intracranial GBM models and would expect comparable efficacy with 16 given its free brain penetration. (13)

Figure 4

Figure 4. Effect of 16 on the PD marker pAKT in the U87 MG/M human glioblastoma xenograft model after 24 days of continuous dosing. Tumors were excised from animals 1 and 4 h after the last administered dose on day 24 and processed for analysis of pAKT as described in the Supporting Information. Indicated values are the means for groups of 3 animals, and error bars indicate ± standard error of the mean. Levels of pAkt (Ser473) and total Akt were measured by electrochemiluminescence using Meso Scale Discovery according to manufacturer’s instructions (Gaithersburg, MD).

To summarize, we have identified 16, a potent purine-based inhibitor of PI3K and mTOR, that is capable of penetrating the BBB. Additionally, 16 has excellent human metabolic stability in microsomal and hepatocyte incubations. Compound 16 demonstrated inhibition of pAKT, a key signal within the PI3K pathway, in both normal brain tissue and in U87 glioblastoma xenograft tumors in mice. Along with pAKT inhibition in U87 tumors, significant tumor growth inhibition was achieved. The promising preclinical profile of 16, along with the significant unmet medical need for glioblastoma treatments, led to the advancement of 16 to clinical development. Details of additional preclinical and clinical studies of 16 will be reported elsewhere.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.6b00005.

  • Assessment of inhibition of 229 kinases by 16, Class I PI3K Kiapps for 16, Western data showing inhibition of pAKT and pS6 in U87 cells by 16, synthetic details and associated analytical data for all reported compounds, experimental details for biochemical and cellular assays, in vitro transport assays, brain and plasma protein binding, PK studies in mice, pAKT/tAKT PD evaluation in mouse brain, and in vivo xenograft studies (PDF)

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

Author Information

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  • Corresponding Author
    • Timothy P. Heffron - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States Email: [email protected]
  • Authors
    • Chudi O. Ndubaku - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Laurent Salphati - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Bruno Alicke - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Jonathan Cheong - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Joy Drobnick - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Kyle Edgar - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Stephen E. Gould - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Leslie B. Lee - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • John D. Lesnick - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Cristina Lewis - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Jim Nonomiya - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Jodie Pang - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Emile G. Plise - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Steve Sideris - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Jeffrey Wallin - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Lan Wang - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Xiaolin Zhang - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
    • Alan G. Olivero - Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
  • Notes
    The authors declare no competing financial interest.

Biography

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Timothy P. Heffron

Timothy P. Heffron is a Senior Scientist at Genentech. As a medicinal chemist, and Chemistry and Research Team Leader, Timothy has advanced programs directed toward treatments for oncology (including cancer immunotherapy), neurology, and ophthalmology indications. Timothy has contributed to seven molecules that have advanced to clinical development, four of which came under his leadership as a chemistry team leader, including taselisib (Phase III). Timothy completed his undergraduate studies in Chemistry at Yale University and his doctoral studies at MIT.

Acknowledgment

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The authors wish to thank Mengling Wong, Chris Hamman, Michael Hayes, and Steve Huhn for compound purification and determination of purity by HPLC, mass spectroscopy, and 1H NMR. We thank Krista K. Bowman, Alberto Estevez, Kyle Mortara, and Jiansheng Wu for technical assistance of protein expression and purification.

ABBREVIATIONS

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PI3K

phosphoinositide 3-kinase

GBM

glioblastoma multiforme

BBB

blood–brain barrier

P-gp

P-glycoprotein

Bcrp

breast cancer resistance protein

mTOR

mammalian target of rapamycin

TPSA

topological polar surface area

dppf

1,1′-bis(diphenylphosphino)ferrocene

References

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This article references 13 other publications.

  1. 1
    Rich, J. N.; Bigner, D. D. Development of Novel Targeted Therapies in the Treament of Malignant Glioma Nat. Rev. Drug Discovery 2004, 3, 430 446

    and references therein.

     DOI: 10.1038/nrd1380
  2. 2
    The Cancer Genome Atlas Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 2008, 455, 1061 1068 DOI: 10.1038/nature07385
  3. 3
    Yap, T. A.; Bjerke, L.; Clarke, P. A.; Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies Curr. Opin. Pharmacol. 2015, 23, 98 107 DOI: 10.1016/j.coph.2015.05.016
  4. 4
    Heffron, T. P.; Salphati, L.; Alicke, B.; Cheong, J.; Dotson, J.; Edgar, J.; Goldsmith, R.; Gould, S. E.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; Ndubaku, C.; Nonomiya, J.; Olivero, A. G.; Pang, J.; Plise, E. G.; Sideris, S.; Trapp, S.; Wallin, J.; Zhang, X. The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α J. Med. Chem. 2012, 55, 8007 8020 DOI: 10.1021/jm300867c
  5. 5
    Sutherlin, D. P.; Bao, L.; Berry, M.; Castanedo, G.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Gunzner, J.; Heffron, T.; Lesnick, J.; Lewis, C.; Mathieu, S.; Murray, J.; Nonomiya, J.; Pang, J.; Pegg, N.; Prior, W. W.; Rouge, L.; Salphati, L.; Sampath, D.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wei, B.; Wiesmann, C.; Wu, P.; Zhu, B.-Y.; Olivero, A. Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhbitor (GDC-0980) for the Treatment of Cancer J. Med. Chem. 2011, 54, 7579 7587 DOI: 10.1021/jm2009327
  6. 6
    Sutherlin, D. P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B.-Y. Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer J. Med. Chem. 2010, 53, 1086 1097 DOI: 10.1021/jm901284w
  7. 7

    In 4-day assays using CellTiter-Glo to monitor proliferation, 16 was studied in the following GBM cell lines: G111, EC50 = 0.27 μM; G96, EC50 = 0.53 μM; G112, EC50 = 0.58 μM; U87, EC50 = 0.74 μM; SF268, EC50 = 1.01 μM; G122, EC50 = 1.01 μM.

  8. 8
    Murray, J. M.; Sweeney, Z. K.; Chan, B. K.; Balazs, M.; Bradley, E.; Castanedo, G.; Chabot, C.; Chantry, D.; Flagella, M.; Goldstein, D. M.; Kondru, R.; Lesnick, J.; Li, J.; Lucas, M. C.; Nonomiya, J.; Pang, J.; Price, S.; Salphati, L.; Safina, B.; Pascal, P. A.; Seward, E. M.; Ultsch, M.; Sutherlin, D. P. Potent and Highly Selective Benzimidazole Inhibitors of PI3-Kinase Delta J. Med. Chem. 2012, 55, 7686 7695 DOI: 10.1021/jm300717c
  9. 9
    Obach, R. S.; Baxter, J. G.; Liston, T. E.; Silber, B. M.; Jones, B. C.; MacIntyre, F.; Rance, D. J.; Wastall, P. The prediction of humanpharmacokinetic parameters from preclinical and in vitro metabolism data J. Pharmacol. Exp. Ther. 1997, 283, 46 58
  10. 10
    Liu, X.; Van Natta, K.; Yeo, H.; Vilenski, O.; Weller, P. E.; Worboys, P. D.; Monshouwer, M. Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid Drug Metab. Dispos. 2009, 37, 787 793 DOI: 10.1124/dmd.108.024125
  11. 11

    Compound 16 was found to have an antiproliferation EC50 of 740 nM in U87 cells. Inhibition of pAKT in U87 cells was demonstrated qualitatively by Western and is included as Supporting Information.

  12. 12
    Lee, J.; Kotilarova, S.; Kotliarov, Y.; Li, A.; Su, Q.; Donin, N. M.; Pastorino, S.; Purow, B. W.; Christopher, N.; Zhang, W.; Park, J. K.; Fine, H. A. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines Cancer Cell 2006, 9, 391 403 DOI: 10.1016/j.ccr.2006.03.030
  13. 13
    Salphati, L.; Heffron, T. P.; Alicke, B.; Nishimura, M.; Barck, K.; Carano, R. A.; Cheong, J.; Edgar, K. A.; Greve, J.; Kharbanda, S.; Koeppen, H.; Lau, S.; Lee, L. B.; Pang; Plise, E. G.; Pokorny, J. L.; Reslan, H. B.; Sarkaria, J. N.; Wallin, J. J.; Zhang, X.; Gould, S. E.; Olivero, A. G.; Phillips, H. S. Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood-Brain Barrier Clin. Cancer Res. 2012, 18, 6239 6248 DOI: 10.1158/1078-0432.CCR-12-0720

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  7. Miao Zhan, Yufang Deng, Lifeng Zhao, Guoyi Yan, Fangying Wang, Ye Tian, Lanxi Zhang, Hongxia Jiang, and Yuanwei Chen . Design, Synthesis, and Biological Evaluation of Dimorpholine Substituted Thienopyrimidines as Potential Class I PI3K/mTOR Dual Inhibitors. Journal of Medicinal Chemistry 2017, 60 (9) , 4023-4035. https://doi.org/10.1021/acs.jmedchem.7b00357
  8. Timothy P. Heffron . Small Molecule Kinase Inhibitors for the Treatment of Brain Cancer. Journal of Medicinal Chemistry 2016, 59 (22) , 10030-10066. https://doi.org/10.1021/acs.jmedchem.6b00618
  9. Andreas Stumpf, Andrew McClory, Herbert Yajima, Nathaniel Segraves, Remy Angelaud, and Francis Gosselin . Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084. Organic Process Research & Development 2016, 20 (4) , 751-759. https://doi.org/10.1021/acs.oprd.6b00011
  10. Timothy P. Heffron Andrew McClory Andreas Stumpf . The Discovery and Process Chemistry Development of GDC-0084, a Brain Penetrating Inhibitor of PI3K and mTOR. 2016, 147-173. https://doi.org/10.1021/bk-2016-1239.ch006
  11. Sabine Mueller, Cassie Kline, Andrea Franson, Jasper van der Lugt, Michael Prados, Sebastian M Waszak, Sabine L A Plasschaert, Annette M Molinaro, Carl Koschmann, Javad Nazarian. Rational combination platform trial design for children and young adults with diffuse midline glioma: A report from PNOC. Neuro-Oncology 2024, 26 (Supplement_2) , S125-S135. https://doi.org/10.1093/neuonc/noad181
  12. Rajappa Kenchappa, Laszlo Radnai, Erica J. Young, Natanael Zarco, Li Lin, Athanassios Dovas, Christian T. Meyer, Ashley Haddock, Alice Hall, Peter Canoll, Michael D. Cameron, Naveen KH Nagaiah, Gavin Rumbaugh, Patrick R. Griffin, Theodore M. Kamenecka, Courtney A. Miller, Steven S. Rosenfeld. MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma. 2024https://doi.org/10.1101/2024.04.27.591399
  13. Gennie L. Parkman, Tursun Turapov, David A. Kircher, William J. Burnett, Christopher M. Stehn, Kayla O'Toole, Katie M. Culver, Ashley T. Chadwick, Riley C. Elmer, Ryan Flaherty, Karly A. Stanley, Mona Foth, David H. Lum, Robert L. Judson-Torres, John E. Friend, Matthew W. VanBrocklin, Martin McMahon, Sheri L. Holmen. Genetic Silencing of AKT Induces Melanoma Cell Death via mTOR Suppression. Molecular Cancer Therapeutics 2024, 23 (3) , 301-315. https://doi.org/10.1158/1535-7163.MCT-23-0474
  14. Laurent Salphati, Jodie Pang, Bruno Alicke, Emile G. Plise, Jonathan Cheong, Allan Jaochico, Alan G. Olivero, Deepak Sampath, Susan Wong, Xiaolin Zhang. Preclinical characterization of the absorption and disposition of the brain penetrant PI3K/mTOR inhibitor paxalisib and prediction of its pharmacokinetics and efficacy in human. Xenobiotica 2024, 54 (2) , 64-74. https://doi.org/10.1080/00498254.2024.2303586
  15. Jiarui Hu, Siyu Fu, Zixuan Zhan, Jifa Zhang. Advancements in dual-target inhibitors of PI3K for tumor therapy: Clinical progress, development strategies, prospects. European Journal of Medicinal Chemistry 2024, 265 , 116109. https://doi.org/10.1016/j.ejmech.2023.116109
  16. Monika Sharma, Ivana Barravecchia, Robert Teis, Jeanette Cruz, Rachel Mumby, Elizabeth K. Ziemke, Carlos E. Espinoza, Varunkumar Krishnamoorthy, Brian Magnuson, Mats Ljungman, Carl Koschmann, Joya Chandra, Christopher E. Whitehead, Judith S. Sebolt-Leopold, Stefanie Galban. Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence. Molecular Cancer Therapeutics 2024, 23 (1) , 24-34. https://doi.org/10.1158/1535-7163.MCT-23-0026
  17. Andressa Letícia Lopes da Silva, Thiago Pina Goes de Araújo, Shakira Cavalcante de Albuquerque Ferreira, Anderson Brandão Leite, João Kaycke Sarmento da Silva, Lilyana Waleska Nunes Albuquerque, Ana Rachel Vasconcelos de Lima, Herbert Charles Silva Barros, Leandro Rocha Silva, Edeildo Ferreira da Silva-Júnior, João Xavier de Araújo-Júnior, Vivaldo Moura Neto, Aline Cavalcanti de Queiroz, Magna Suzana Alexandre-Moreira. PI3K Signaling Pathways as a Molecular Target for Glioblastoma Multiforme. Current Protein & Peptide Science 2024, 25 (1) , 12-26. https://doi.org/10.2174/1389203724666230830125102
  18. Xueqin Huang, Li You, Eugenie Nepovimova, Miroslav Psotka, David Malinak, Marian Valko, Ladislav Sivak, Jan Korabecny, Zbynek Heger, Vojtech Adam, Qinghua Wu, Kamil Kuca. Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK). Journal of Enzyme Inhibition and Medicinal Chemistry 2023, 38 (1) https://doi.org/10.1080/14756366.2023.2237209
  19. Judith Schaf, Sonia Shinhmar, Qingyu Zeng, Olivier E. Pardo, Philip Beesley, Nelofer Syed, Robin S. B. Williams. Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth. Cell Death Discovery 2023, 9 (1) https://doi.org/10.1038/s41420-023-01462-6
  20. Brittany Dewdney, Misty R. Jenkins, Sarah A. Best, Saskia Freytag, Krishneel Prasad, Jeff Holst, Raelene Endersby, Terrance G. Johns. From signalling pathways to targeted therapies: unravelling glioblastoma’s secrets and harnessing two decades of progress. Signal Transduction and Targeted Therapy 2023, 8 (1) https://doi.org/10.1038/s41392-023-01637-8
  21. Tongxuan Guo, Changyong Wu, Junhao Zhang, Jiefeng Yu, Guoxi Li, Hongyan Jiang, Xu Zhang, Rutong Yu, Xuejiao Liu. Dual blockade of EGFR and PI3K signaling pathways offers a therapeutic strategy for glioblastoma. Cell Communication and Signaling 2023, 21 (1) https://doi.org/10.1186/s12964-023-01400-0
  22. Shilpi Singh, Debashis Barik, Karl Lawrie, Iteeshree Mohapatra, Sujata Prasad, Afsar R. Naqvi, Amar Singh, Gatikrushna Singh. Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment. International Journal of Molecular Sciences 2023, 24 (19) , 14960. https://doi.org/10.3390/ijms241914960
  23. Julia A. Schulz, Anika M.S. Hartz, Björn Bauer, . ABCB1 and ABCG2 Regulation at the Blood-Brain Barrier: Potential New Targets to Improve Brain Drug Delivery. Pharmacological Reviews 2023, 75 (5) , 815-853. https://doi.org/10.1124/pharmrev.120.000025
  24. Vinod A. B., Arunava Das. Validated liquid chromatography with tandem mass spectrometry method for determination of paxalisib in mouse plasma: An application to pharmacokinetic study in mice. Biomedical Chromatography 2023, 37 (8) https://doi.org/10.1002/bmc.5650
  25. Christian Grommes, Elena Pentsova, Lauren R. Schaff, Craig P. Nolan, Thomas Kaley, Anne S. Reiner, Katherine S. Panageas, Ingo K. Mellinghoff. Preclinical and clinical evaluation of Buparlisib (BKM120) in recurrent/refractory Central Nervous System Lymphoma. Leukemia & Lymphoma 2023, 64 (9) , 1545-1553. https://doi.org/10.1080/10428194.2023.2223734
  26. M.H. Ahmed, M. Canney, A. Carpentier, A. Idbaih. Overcoming the blood brain barrier in glioblastoma: Status and future perspective. Revue Neurologique 2023, 179 (5) , 430-436. https://doi.org/10.1016/j.neurol.2023.03.013
  27. Estrella Gonzales-Aloy, Aria Ahmed-Cox, Maria Tsoli, David S. Ziegler, Maria Kavallaris. From cells to organoids: The evolution of blood-brain barrier technology for modelling drug delivery in brain cancer. Advanced Drug Delivery Reviews 2023, 196 , 114777. https://doi.org/10.1016/j.addr.2023.114777
  28. Aditya Raj, Adarsh Kumar, Ankit Kumar Singh, Harshwardhan Singh, Suresh Thareja, Pradeep Kumar. Synthetic Methodologies and SAR of Quinazoline Derivatives as PI3K Inhibitors. Anti-Cancer Agents in Medicinal Chemistry 2023, 23 (9) , 1013-1047. https://doi.org/10.2174/1871520623666230116163424
  29. Paula Alfonso-Triguero, Julia Lorenzo, Ana Paula Candiota, Carles Arús, Daniel Ruiz-Molina, Fernando Novio. Platinum-Based Nanoformulations for Glioblastoma Treatment: The Resurgence of Platinum Drugs?. Nanomaterials 2023, 13 (10) , 1619. https://doi.org/10.3390/nano13101619
  30. Ashok Zakkula, Harsha K. Tripathy, Rama Murthi Bestha, A. B. Vinod, Vinay Kiran, Sreekanth Dittakavi, Ramesh Mullangi. Validated HPLC‐UV method for quantification of paxalisib, a pan PI3K and mTOR inhibitor in mouse plasma: Application to a pharmacokinetic study in mice. Biomedical Chromatography 2023, 37 (4) https://doi.org/10.1002/bmc.5587
  31. Min Chen, Huanrong Lan, Shiya Yao, Ketao Jin, Yun Chen. Metabolic Interventions in Tumor Immunity: Focus on Dual Pathway Inhibitors. Cancers 2023, 15 (7) , 2043. https://doi.org/10.3390/cancers15072043
  32. Fabio Raith, Daniel H. O’Donovan, Clara Lemos, Oliver Politz, Bernard Haendler. Addressing the Reciprocal Crosstalk between the AR and the PI3K/AKT/mTOR Signaling Pathways for Prostate Cancer Treatment. International Journal of Molecular Sciences 2023, 24 (3) , 2289. https://doi.org/10.3390/ijms24032289
  33. Barbara Jonchere, Justin Williams, Frederique Zindy, Jingjing Liu, Sarah Robinson, Dana M. Farmer, Jaeki Min, Lei Yang, Jennifer L. Stripay, Yingzhe Wang, Burgess B. Freeman, Jiyang Yu, Anang A. Shelat, Zoran Rankovic, Martine F. Roussel. Combination of Ribociclib with BET-Bromodomain and PI3K/mTOR Inhibitors for Medulloblastoma Treatment In Vitro and In Vivo. Molecular Cancer Therapeutics 2023, 22 (1) , 37-51. https://doi.org/10.1158/1535-7163.MCT-21-0896
  34. Maria Antonietta Occhiuzzi, Gernando Lico, Giuseppina Ioele, Michele De Luca, Antonio Garofalo, Fedora Grande. Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents. European Journal of Medicinal Chemistry 2023, 246 , 114971. https://doi.org/10.1016/j.ejmech.2022.114971
  35. Xianbo Wu, Yihua Xu, Qi Liang, Xinwei Yang, Jianli Huang, Jie Wang, Hong Zhang, Jianyou Shi. Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment. Frontiers in Pharmacology 2022, 13 https://doi.org/10.3389/fphar.2022.875372
  36. Monica M. Kangussu-Marcolino, Upinder Singh. Ponatinib, Lestaurtinib, and mTOR/PI3K Inhibitors Are Promising Repurposing Candidates against Entamoeba histolytica. Antimicrobial Agents and Chemotherapy 2022, 66 (2) https://doi.org/10.1128/AAC.01207-21
  37. Marcian E. Van Dort, Youngsoon Jang, Christopher A. Bonham, Kevin Heist, Dilrukshika S.W. Palagama, Lucas McDonald, Edward Z. Zhang, Thomas L. Chenevert, Gary D. Luker, Brian D. Ross. Structural effects of morpholine replacement in ZSTK474 on Class I PI3K isoform inhibition: Development of novel MEK/PI3K bifunctional inhibitors. European Journal of Medicinal Chemistry 2022, 229 , 113996. https://doi.org/10.1016/j.ejmech.2021.113996
  38. Amir Barzegar Behrooz, Zahra Talaie, Fatemeh Jusheghani, Marek J. Łos, Thomas Klonisch, Saeid Ghavami. Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma. International Journal of Molecular Sciences 2022, 23 (3) , 1353. https://doi.org/10.3390/ijms23031353
  39. Emanuela B. Pucko, Robert P. Ostrowski. Inhibiting CK2 among Promising Therapeutic Strategies for Gliomas and Several Other Neoplasms. Pharmaceutics 2022, 14 (2) , 331. https://doi.org/10.3390/pharmaceutics14020331
  40. Surabhi Talele, Afroz S. Mohammad, Julia A. Schulz, Bjoern Bauer, Anika M. S. Hartz, Jann N. Sarkaria, William F. Elmquist. Drug Delivery to Primary and Metastatic Brain Tumors: Challenges and Opportunities. 2022, 723-762. https://doi.org/10.1007/978-3-030-88773-5_24
  41. Jarosław Sączewski, Joanna Fedorowicz. Three Heterocyclic Rings Fused (6-5-6). 2022, 569-596. https://doi.org/10.1016/B978-0-12-409547-2.14881-4
  42. Ok Kyoung Choi, Yong Ho Sun, Hyemi Lee, Joon Kwang Lee, Tae Hoon Lee, Hakwon Kim. Synthesis of Novel (S)-3-(1-Aminoethyl)-8-pyrimidinyl-2-phenylisoquinolin-1(2H)-ones by Suzuki–Miyaura Coupling and Their Cell Toxicity Activities. Pharmaceuticals 2022, 15 (1) , 64. https://doi.org/10.3390/ph15010064
  43. Dandan Meng, Wei He, Yan Zhang, Zhenguo Liang, Jinling Zheng, Xu Zhang, Xing Zheng, Peng Zhan, Hongfei Chen, Wenjun Li, Lintao Cai. Development of PI3K inhibitors: Advances in clinical trials and new strategies (Review). Pharmacological Research 2021, 173 , 105900. https://doi.org/10.1016/j.phrs.2021.105900
  44. Chiara Borsari, Martina De Pascale, Matthias P. Wymann. Chemical and Structural Strategies to Selectively Target mTOR Kinase. ChemMedChem 2021, 16 (18) , 2744-2759. https://doi.org/10.1002/cmdc.202100332
  45. Chengze Tian, Chengbin Yang, Tianze Wu, Mingzhu Lu, Yi Chen, Yongtai Yang, Xiaofeng Liu, Yun Ling, Mingli Deng, Yu Jia, Yaming Zhou. Discovery of cinnoline derivatives as potent PI3K inhibitors with antiproliferative activity. Bioorganic & Medicinal Chemistry Letters 2021, 48 , 128271. https://doi.org/10.1016/j.bmcl.2021.128271
  46. Eclair Venturini Filho, Erick M.C. Pinheiro, Sergio Pinheiro, Sandro J. Greco. Aminopyrimidines: Recent synthetic procedures and anticancer activities. Tetrahedron 2021, 92 , 132256. https://doi.org/10.1016/j.tet.2021.132256
  47. Jianling Xie, Eric P. Kusnadi, Luc Furic, Luke A. Selth. Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer. Cancers 2021, 13 (13) , 3254. https://doi.org/10.3390/cancers13133254
  48. Mayra Colardo, Marco Segatto, Sabrina Di Bartolomeo. Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update. International Journal of Molecular Sciences 2021, 22 (9) , 4899. https://doi.org/10.3390/ijms22094899
  49. Rachel K. Surowiec, Sarah F. Ferris, April Apfelbaum, Carlos Espinoza, Ranjit K. Mehta, Karamoja Monchamp, Veerin R. Sirihorachai, Karan Bedi, Mats Ljungman, Stefanie Galban. Transcriptomic Analysis of Diffuse Intrinsic Pontine Glioma (DIPG) Identifies a Targetable ALDH-Positive Subset of Highly Tumorigenic Cancer Stem-like Cells. Molecular Cancer Research 2021, 19 (2) , 223-239. https://doi.org/10.1158/1541-7786.MCR-20-0464
  50. Yifan Chen, Xiaoping Zhou. Research progress of mTOR inhibitors. European Journal of Medicinal Chemistry 2020, 208 , 112820. https://doi.org/10.1016/j.ejmech.2020.112820
  51. Benjamin M. Ellingson, Jingwen Yao, Catalina Raymond, David A. Nathanson, Ararat Chakhoyan, Jeremy Simpson, James S. Garner, Alan G. Olivero, Lars U. Mueller, Jordi Rodon, Elizabeth Gerstner, Timothy F. Cloughesy, Patrick Y. Wen. Multiparametric MR-PET Imaging Predicts Pharmacokinetics and Clinical Response to GDC-0084 in Patients with Recurrent High-Grade Glioma. Clinical Cancer Research 2020, 26 (13) , 3135-3144. https://doi.org/10.1158/1078-0432.CCR-19-3817
  52. Patrick Y. Wen, Timothy F. Cloughesy, Alan G. Olivero, Kari M. Morrissey, Timothy R. Wilson, Xuyang Lu, Lars U. Mueller, Alexandre F. Coimbra, Benjamin M. Ellingson, Elizabeth Gerstner, Eudocia Q. Lee, Jordi Rodon. First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma. Clinical Cancer Research 2020, 26 (8) , 1820-1828. https://doi.org/10.1158/1078-0432.CCR-19-2808
  53. Chiara Tarantelli, Antonio Lupia, Anastasios Stathis, Francesco Bertoni. Is There a Role for Dual PI3K/mTOR Inhibitors for Patients Affected with Lymphoma?. International Journal of Molecular Sciences 2020, 21 (3) , 1060. https://doi.org/10.3390/ijms21031060
  54. Bo Zhong, Olivia Campagne, Christopher L. Tinkle, Clinton F. Stewart. An LC/ESI–MS/MS method to quantify the PI3K inhibitor GDC‐0084 in human plasma and cerebrospinal fluid: Validation and clinical application. Biomedical Chromatography 2020, 34 (1) https://doi.org/10.1002/bmc.4697
  55. Jean-Marie Nicolas, Hugues Chanteux, Johan Nicolaï, Frédéric Brouta, Delphine Viot, Marie-Luce Rosseels, Eric Gillent, Pierre Bonnaillie, François-Xavier Mathy, Jeff Long, Eric Helmer. Role of P-glycoprotein in the brain disposition of seletalisib: Evaluation of the potential for drug-drug interactions. European Journal of Pharmaceutical Sciences 2020, 142 , 105122. https://doi.org/10.1016/j.ejps.2019.105122
  56. Monica M. Kangussu-Marcolino, Gretchen M. Ehrenkaufer, Emily Chen, Anjan Debnath, Upinder Singh. Identification of plicamycin, TG02, panobinostat, lestaurtinib, and GDC-0084 as promising compounds for the treatment of central nervous system infections caused by the free-living amebae Naegleria, Acanthamoeba and Balamuthia. International Journal for Parasitology: Drugs and Drug Resistance 2019, 11 , 80-94. https://doi.org/10.1016/j.ijpddr.2019.10.003
  57. Burgess B. Freeman, Lei Yang, Zoran Rankovic. Practical approaches to evaluating and optimizing brain exposure in early drug discovery. European Journal of Medicinal Chemistry 2019, 182 , 111643. https://doi.org/10.1016/j.ejmech.2019.111643
  58. Ana Paula M. Nascimento, Ingrid A.V. Wolin, Priscilla G. Welter, Isabella A. Heinrich, Alfeu Zanotto-Filho, Vinicius J.S. Osterne, Claudia F. Lossio, Mayara T.L. Silva, Kyria S. Nascimento, Benildo S. Cavada, Rodrigo B. Leal. Lectin from Dioclea violacea induces autophagy in U87 glioma cells. International Journal of Biological Macromolecules 2019, 134 , 660-672. https://doi.org/10.1016/j.ijbiomac.2019.04.203
  59. Franziska M. Ippen, Christopher A. Alvarez-Breckenridge, Benjamin M. Kuter, Alexandria L. Fink, Ivanna V. Bihun, Matthew Lastrapes, Tristan Penson, Stephen P. Schmidt, Gregory R. Wojtkiewicz, Jianfang Ning, Megha Subramanian, Anita Giobbie-Hurder, Maria Martinez-Lage, Scott L. Carter, Daniel P. Cahill, Hiroaki Wakimoto, Priscilla K. Brastianos. The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA -Mutant Breast Cancer Brain Metastases. Clinical Cancer Research 2019, 25 (11) , 3374-3383. https://doi.org/10.1158/1078-0432.CCR-18-3049
  60. Hamza Saleem, U. Kulsoom Abdul, Asli Küçükosmanoglu, Megan Houweling, Fleur M.G. Cornelissen, Dieter H. Heiland, Monika E. Hegi, Mathilde C.M. Kouwenhoven, David Bailey, Tom Würdinger, Bart A. Westerman. The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation. Drug Resistance Updates 2019, 43 , 29-37. https://doi.org/10.1016/j.drup.2019.04.002
  61. Eric D. Slack, Peter D. Tancini, Thomas J. Colacot. Process Economics and Atom Economy for Industrial Cross Coupling Applications via LnPd(0)-Based Catalysts. 2019, 161-198. https://doi.org/10.1007/3418_2019_28
  62. Mark C. de Gooijer, Ping Zhang, Levi C. M. Buil, Ceren H. Çitirikkaya, Nishita Thota, Jos H. Beijnen, Olaf van Tellingen. Buparlisib is a brain penetrable pan-PI3K inhibitor. Scientific Reports 2018, 8 (1) https://doi.org/10.1038/s41598-018-29062-w
  63. . Phase‐Transfer Catalysis. 2018, 359-386. https://doi.org/10.1002/9783527807253.ch11
  64. Edouard Alphandéry. Glioblastoma Treatments: An Account of Recent Industrial Developments. Frontiers in Pharmacology 2018, 9 https://doi.org/10.3389/fphar.2018.00879
  65. Ling-tao Ding, Peng Zhao, Min-lie Yang, Guo-zhong Lv, Tian-lan Zhao. GDC-0084 inhibits cutaneous squamous cell carcinoma cell growth. Biochemical and Biophysical Research Communications 2018, 503 (3) , 1941-1948. https://doi.org/10.1016/j.bbrc.2018.07.139
  66. Andrew Smith, Mercy Pawar, Marcian E. Van Dort, Stefanie Galbán, Amanda R. Welton, Greg M. Thurber, Brian D. Ross, Cagri G. Besirli. Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors. Journal of Ocular Pharmacology and Therapeutics 2018, 34 (6) , 477-485. https://doi.org/10.1089/jop.2017.0126
  67. Andrea Shergalis, Armand Bankhead, Urarika Luesakul, Nongnuj Muangsin, Nouri Neamati, . Current Challenges and Opportunities in Treating Glioblastoma. Pharmacological Reviews 2018, 70 (3) , 412-445. https://doi.org/10.1124/pr.117.014944
  68. Yuan Shi, Mary Mader. Brain penetrant kinase inhibitors: Learning from kinase neuroscience discovery. Bioorganic & Medicinal Chemistry Letters 2018, 28 (11) , 1981-1991. https://doi.org/10.1016/j.bmcl.2018.05.007
  69. Fleur M. Ferguson, Nathanael S. Gray. Kinase inhibitors: the road ahead. Nature Reviews Drug Discovery 2018, 17 (5) , 353-377. https://doi.org/10.1038/nrd.2018.21
  70. Timothy P Heffron. Challenges of developing small-molecule kinase inhibitors for brain tumors and the need for emphasis on free drug levels. Neuro-Oncology 2018, 20 (3) , 307-312. https://doi.org/10.1093/neuonc/nox179
  71. Milan Jovanović, Katarina Nikolić, Žarko Gagić, Danica Agbaba. Molecular modeling and analysis of the 3D pharmacophore structure of the selective PI3K-α inhibitors as antitumor agents. Arhiv za farmaciju 2018, 68 (4) , 860-873. https://doi.org/10.5937/ArhFarm1804860J
  72. Joshua R D Pearson, Tarik Regad. Targeting cellular pathways in glioblastoma multiforme. Signal Transduction and Targeted Therapy 2017, 2 (1) https://doi.org/10.1038/sigtrans.2017.40
  73. Hua-fu Zhao, Jing Wang, Wei Shao, Chang-peng Wu, Zhong-ping Chen, Shing-shun Tony To, Wei-ping Li. Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. Molecular Cancer 2017, 16 (1) https://doi.org/10.1186/s12943-017-0670-3
  74. A.A. Mortlock, D.M. Wilson, J.G. Kettle, F.W. Goldberg, K.M. Foote. Selective Kinase Inhibitors in Cancer. 2017, 39-75. https://doi.org/10.1016/B978-0-12-409547-2.12391-1
  75. H. Tsui, Q. Zeng, K. Chen, X. Zhang. Inhibiting Kinases in the CNS. 2017, 408-446. https://doi.org/10.1016/B978-0-12-409547-2.13815-6
  76. Laurent Salphati, Bruno Alicke, Timothy P. Heffron, Sheerin Shahidi-Latham, Merry Nishimura, Tim Cao, Richard A. Carano, Jonathan Cheong, Joan Greve, Hartmut Koeppen, Shari Lau, Leslie B. Lee, Michelle Nannini-Pepe, Jodie Pang, Emile G. Plise, Cristine Quiason, Linda Rangell, Xiaolin Zhang, Stephen E. Gould, Heidi S. Phillips, Alan G. Olivero. Brain Distribution and Efficacy of the Brain Penetrant PI3K Inhibitor GDC-0084 in Orthotopic Mouse Models of Human Glioblastoma. Drug Metabolism and Disposition 2016, 44 (12) , 1881-1889. https://doi.org/10.1124/dmd.116.071423
  • Abstract

    Scheme 1

    Scheme 1. Synthetic Route to Obtain Tricyclic Purine-Based Brain Penetrant PI3K Inhibitor 16

    Figure 1

    Figure 1. CNS penetration of 16 in rat and mouse. [Brain]/[Plasma] ratios determined after oral dose of 16 to female CD-1 mice or male Sprague–Dawley rats as an MCT suspension. *[Brain]u and [Plasma]u refer to the unbound concentration measured in the brain and plasma, respectively. **[CSF] refers to the concentration measured in the cerebral spinal fluid. aDetermined to be identical at both 1 and 6 h after administration of 25 mg/kg 16 to female CD-1 mice. The [Brain]/[Plasma] ratios are the mean values from 3 animals per time point. bDetermined after administration of 15 mg/kg 16 to male Sprague–Dawley rats. [Brain]/[Plasma] determined for 1 animal at each of 0.25 and 2 h and 3 at 8 h. Data reported are the range across the three time points (average of the 3 animals at 8 h). c[CSF] determined for 1 animal at each of 0.25 and 2 h and 3 at 8 h. Data reported are the range across the three time points (average of the 3 animals at 8 h).

    Figure 2

    Figure 2. Inhibition of p-AKT by 16 in normal mouse brain tissue along with corresponding brain and unbound brain concentrations. *Significantly different from untreated control. p < 0.05, t test. [Brain] determined after 25 mg/kg oral dose of 16 female CD-1 mice as an MCT suspension. [Brain]u refers to the unbound concentration measured in the brain. Data are reported as mean values ± SD from 3 animals per time point.

    Figure 3

    Figure 3. In vivo efficacy of 16 versus U87 MG/M human glioblastoma xenografts. Female NCr nude mice bearing subcutaneous tumors were administered escalating doses of 16 orally as a suspension in vehicle (0.5% methylcellulose/0.2% Tween-80) or vehicle once daily (QD) for 23 days. Changes in tumor volumes over time by dose for each compound are depicted as cubic spline fits generated via Linear Mixed Effects analysis of log-transformed volumes.

    Figure 4

    Figure 4. Effect of 16 on the PD marker pAKT in the U87 MG/M human glioblastoma xenograft model after 24 days of continuous dosing. Tumors were excised from animals 1 and 4 h after the last administered dose on day 24 and processed for analysis of pAKT as described in the Supporting Information. Indicated values are the means for groups of 3 animals, and error bars indicate ± standard error of the mean. Levels of pAkt (Ser473) and total Akt were measured by electrochemiluminescence using Meso Scale Discovery according to manufacturer’s instructions (Gaithersburg, MD).

  • References

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    Jump To

    This article references 13 other publications.

    1. 1
      Rich, J. N.; Bigner, D. D. Development of Novel Targeted Therapies in the Treament of Malignant Glioma Nat. Rev. Drug Discovery 2004, 3, 430 446

      and references therein.

       DOI: 10.1038/nrd1380
    2. 2
      The Cancer Genome Atlas Network Comprehensive genomic characterization defines human glioblastoma genes and core pathways Nature 2008, 455, 1061 1068 DOI: 10.1038/nature07385
    3. 3
      Yap, T. A.; Bjerke, L.; Clarke, P. A.; Workman, P. Drugging PI3K in cancer: refining targets and therapeutic strategies Curr. Opin. Pharmacol. 2015, 23, 98 107 DOI: 10.1016/j.coph.2015.05.016
    4. 4
      Heffron, T. P.; Salphati, L.; Alicke, B.; Cheong, J.; Dotson, J.; Edgar, J.; Goldsmith, R.; Gould, S. E.; Lee, L. B.; Lesnick, J. D.; Lewis, C.; Ndubaku, C.; Nonomiya, J.; Olivero, A. G.; Pang, J.; Plise, E. G.; Sideris, S.; Trapp, S.; Wallin, J.; Zhang, X. The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α J. Med. Chem. 2012, 55, 8007 8020 DOI: 10.1021/jm300867c
    5. 5
      Sutherlin, D. P.; Bao, L.; Berry, M.; Castanedo, G.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Gunzner, J.; Heffron, T.; Lesnick, J.; Lewis, C.; Mathieu, S.; Murray, J.; Nonomiya, J.; Pang, J.; Pegg, N.; Prior, W. W.; Rouge, L.; Salphati, L.; Sampath, D.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wei, B.; Wiesmann, C.; Wu, P.; Zhu, B.-Y.; Olivero, A. Discovery of a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhbitor (GDC-0980) for the Treatment of Cancer J. Med. Chem. 2011, 54, 7579 7587 DOI: 10.1021/jm2009327
    6. 6
      Sutherlin, D. P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B.-Y. Discovery of (Thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer J. Med. Chem. 2010, 53, 1086 1097 DOI: 10.1021/jm901284w
    7. 7

      In 4-day assays using CellTiter-Glo to monitor proliferation, 16 was studied in the following GBM cell lines: G111, EC50 = 0.27 μM; G96, EC50 = 0.53 μM; G112, EC50 = 0.58 μM; U87, EC50 = 0.74 μM; SF268, EC50 = 1.01 μM; G122, EC50 = 1.01 μM.

    8. 8
      Murray, J. M.; Sweeney, Z. K.; Chan, B. K.; Balazs, M.; Bradley, E.; Castanedo, G.; Chabot, C.; Chantry, D.; Flagella, M.; Goldstein, D. M.; Kondru, R.; Lesnick, J.; Li, J.; Lucas, M. C.; Nonomiya, J.; Pang, J.; Price, S.; Salphati, L.; Safina, B.; Pascal, P. A.; Seward, E. M.; Ultsch, M.; Sutherlin, D. P. Potent and Highly Selective Benzimidazole Inhibitors of PI3-Kinase Delta J. Med. Chem. 2012, 55, 7686 7695 DOI: 10.1021/jm300717c
    9. 9
      Obach, R. S.; Baxter, J. G.; Liston, T. E.; Silber, B. M.; Jones, B. C.; MacIntyre, F.; Rance, D. J.; Wastall, P. The prediction of humanpharmacokinetic parameters from preclinical and in vitro metabolism data J. Pharmacol. Exp. Ther. 1997, 283, 46 58
    10. 10
      Liu, X.; Van Natta, K.; Yeo, H.; Vilenski, O.; Weller, P. E.; Worboys, P. D.; Monshouwer, M. Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid Drug Metab. Dispos. 2009, 37, 787 793 DOI: 10.1124/dmd.108.024125
    11. 11

      Compound 16 was found to have an antiproliferation EC50 of 740 nM in U87 cells. Inhibition of pAKT in U87 cells was demonstrated qualitatively by Western and is included as Supporting Information.

    12. 12
      Lee, J.; Kotilarova, S.; Kotliarov, Y.; Li, A.; Su, Q.; Donin, N. M.; Pastorino, S.; Purow, B. W.; Christopher, N.; Zhang, W.; Park, J. K.; Fine, H. A. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines Cancer Cell 2006, 9, 391 403 DOI: 10.1016/j.ccr.2006.03.030
    13. 13
      Salphati, L.; Heffron, T. P.; Alicke, B.; Nishimura, M.; Barck, K.; Carano, R. A.; Cheong, J.; Edgar, K. A.; Greve, J.; Kharbanda, S.; Koeppen, H.; Lau, S.; Lee, L. B.; Pang; Plise, E. G.; Pokorny, J. L.; Reslan, H. B.; Sarkaria, J. N.; Wallin, J. J.; Zhang, X.; Gould, S. E.; Olivero, A. G.; Phillips, H. S. Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood-Brain Barrier Clin. Cancer Res. 2012, 18, 6239 6248 DOI: 10.1158/1078-0432.CCR-12-0720
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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.6b00005.

    • Assessment of inhibition of 229 kinases by 16, Class I PI3K Kiapps for 16, Western data showing inhibition of pAKT and pS6 in U87 cells by 16, synthetic details and associated analytical data for all reported compounds, experimental details for biochemical and cellular assays, in vitro transport assays, brain and plasma protein binding, PK studies in mice, pAKT/tAKT PD evaluation in mouse brain, and in vivo xenograft studies (PDF)


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