Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors

Journal of Medicinal Chemistry

Volumn 55, Issue 18, 2012, Pages 8110-8127

  Blake, James F ^a   Xu, Rui ^a   Bencsik, Josef R ^a   Xiao, Dengming ^a   Kallan, Nicholas C ^a   Schlachter, Stephen ^a   Mitchell, Ian S ^a   Spencer, Keith L ^a   Banka, Anna L ^a   Wallace, Eli M ^a   Gloor, Susan L ^a   Martinson, Matthew ^a   Woessner, Richard D ^a   Vigers, Guy P A ^a   Brandhuber, Barbara J ^a   Liang, Jun ^b   Safina, Brian S ^b   Li, Jun ^b   Zhang, Birong ^b   Chabot, Christine ^b   Do, Steven ^b   Lee, Leslie ^b   Oeh, Jason ^b   Sampath, Deepak ^b   Lee, Brian B ^b   Lin, Kui ^b   Liederer, Bianca M ^b   Skelton, Nicholas J ^b   more..

^a ARRAY BIOPHARMA INC   (United States)

^b GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2(4 CHLOROPHENYL) 1[4(7 HYDROXY 5 METHYL 6,7 DIHYDRO 5H CYCLOPENTA [D] PYRIMIDIN 4 YL) PIPERAZIN 1 YL] 3 (ISOPROPYLAMINO) PROPAN 1 ONE; GDC 0068; MAMMALIAN TARGET OF RAPAMYCIN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL; CANCER INHIBITION; CONTROLLED STUDY; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG IDENTIFICATION; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; IC 50; KINETICS; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; PROSTATE CANCER; STEREOCHEMISTRY; TUMOR XENOGRAFT;

ADENOSINE TRIPHOSPHATE; ANTINEOPLASTIC AGENTS; BINDING, COMPETITIVE; DRUG DISCOVERY; HUMANS; INHIBITORY CONCENTRATION 50; MODELS, MOLECULAR; PROTEIN CONFORMATION; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; PYRIMIDINES; SUBSTRATE SPECIFICITY;

EID: 84866863731     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301024w     Document Type: Article

References (28)

1. Cheng, J. Q.; Lindsley, C. W.; Cheng, G. Z.; Yang, H.; Nicosia, S. V. The Akt/PKB pathway: molecular target for cancer drug discovery Oncogene 2005, 24, 7482-7492
2. Manning, B. D.; Cantley, L. C. AKT/PKB signaling: navigating downstream Cell 2007, 129, 1261-1274
3. Altomare, D. A.; Testa, J. R. Perturbations of the AKT signaling pathway in human cancer Oncogene 2005, 24, 7455-7464
4. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer Nat. Rev. Cancer 2002, 2, 489-501
5. Lian, Z.; Di Cristofano, A. Class reunion: PTEN joins the nuclear crew Oncogene 2005, 24, 7394-7400
6. Degtyarev, M.; De Mazière, A.; Orr, C.; Lin, J.; Lee, B. B.; Tien, J. Y.; Prior, W. W.; van Dijk, S.; Wu, H.; Gray, D. C.; Davis, D. P.; Stern, H. M.; Murray, L. J.; Hoeflich, K. P.; Klumperman, J.; Friedman, L. S.; Lin, K. Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents J. Cell Biol. 2008, 183, 101-16
7. Chen, Y. L.; Law, P. -Y; Loh, H. H. Inhibition of PI3K/Akt signaling: an emerging paradigm for targeted cancer therapy Curr. Med. Chem. Anticancer Agents 2005, 5, 575-589
8. Lu, Y.; Wang, H.; Mills, G. B. Targeting PI3K-AKT pathway for cancer therapy Rev. Clin. Exp. Hematol. 2003, 7, 205-228
9. Mitsiades, C. S.; Mitsiades, N.; Koutsilieris, M.; Nicholson, K. M.; Anderson, N. G.; Neri, L. M.; Borgatti, P.; Capitani, S.; Martelli, M.; Brazil, D. P.; Hemmings, B. A. The Akt pathway: molecular targets for anti-cancer drug development Curr. Cancer Drug Targets 2004, 4, 235-256
10. Pal, S. K.; Reckamp, K.; Yu, H.; Figlin, R. A. Akt inhibitors in clinical development for the treatment of cancer Expert Opin. Invest. Drugs 2010, 19, 1355-1366
11. Blake, J. F.; Kallan, N. C.; Xiao, D.; Xu, R.; Bencsik, J. R.; Skelton, N. J.; Spencer, K. L.; Mitchell, I. S.; Woessner, R. D.; Gloor, S. L.; Risom, T.; Gross, S. D.; Martinson, M.; Morales, T. H.; Vigers, G. P. A.; Brandhuber, B. J. Discovery of pyrrolopyrimidine inhibitors of Akt Bioorg. Med. Chem. Lett. 2010, 20, 5607-5612
12. Bencsik, J. R.; Xiao, D.; Blake, J. F.; Kallan, N. C.; Mitchell, I. S.; Spencer, K. L.; Xu, R.; Gloor, S. L.; Martinson, M.; Risom, T.; Woessner, R. D.; Dizon, F.; Wu, W.-I.; Vigers, G. P. A.; Brandhuber, B. J.; Skelton, N. J.; Prior, W. W.; Murray, L. J. Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 7037-7041
13. Taber, D. F.; Petty, E. H. General route to highly functionalized cyclopentane derivatives by intermolecular C-H insertion J. Org. Chem. 1982, 47, 4808-4809
14. Nugent, W. A.; Hobbs, F. W., Jr. Improved route to 3-vinyl substituted cyclopentanones. Synthesis of (±)-mitsugashiwalactone J. Org. Chem. 1986, 51, 3376-3378
15. Yin, J.; Zarkowsky, D. S.; Thomas, D. W.; Zhao, M. M.; Huffman, M. A. Direct and convenient conversion of alcohols to fluorides Org. Lett. 2004, 6, 1465-1468
16. Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. Ruthenium (II)-catalyzed asymmetric transfer hydrogenation of ketones using a formic acid-triethylamine mixture J. Am. Chem. Soc. 1996, 118, 2521-2522
17. Middleton, W. J. New fluorinating reagents. Dialkylaminosulfur fluorides J. Org. Chem. 1975, 40, 574-578
18. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. A convenient method for synthesis of enantiomerically enriched methylphenidate from N -methoxycarbonylpiperidine Org. Lett. 1999, 1, 175-178
19. Matsumura, Y.; Kanda, Y.; Shirai, K.; Onomura, O.; Maki, T. A convenient method for synthesis of optically active methylphenidate from N -methoxycarbonylpiperidine by utilizing electrochemical oxidation and Evans aldol-type reaction Tetrahedron 2000, 56, 7411-7422
20. Pilli, R. A.; Böckelmann, M. A.; de Fatima Alves, C. The stereochemistry of the addition of chlorotitanium enolates of N -acyl oxazolidin-2-ones to 5- and 6-membered N -acyliminium ions J. Braz. Chem. Soc. 2001, 12, 634-651
21. Kallan, N. C.; Spencer, K. L.; Blake, J. F.; Xu, R.; Heizer, J.; Bencsik, J. R.; Mitchell, I. S.; Gloor, S. L.; Martinson, M.; Risom, T.; Gross, S. D.; Morales, T. H.; Vigers, G. P. A.; Brandhuber, B. J.; Skelton, N. J. Discovery and SAR of spirochromane Akt inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 2410-2414
22. a modulation of new chemical series Eur. J. Med. Chem. 2010, 45, 4270-4279
23. Zeng, Q.; Bourbeau, M. P.; Wohlhieter, G. E.; Yao, G.; Monenschein, H.; Rider, J. T.; Lee, M. R.; Zhang, S.; Lofgren, J.; Freeman, D.; Li, C.; Tominey, E.; Huang, X.; Hoffman, D.; Yamane, H.; Tasker, A. S.; Dominguez, C.; Viswanadhan, V. N.; Hungate, R.; Zhang, X. 2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics Bioorg. Med. Chem. Lett. 2010, 20, 1652-1656
24. Han, E. K-H.; Leverson, J. D.; McGonigal1, T.; Shah, O. J.; Woods, K. W.; Hunter, T.; Giranda, V. L.; Luo, Y. Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition Oncogene 2007, 26, 5655-5661
25. Rhodes, N.; Heerding, D. A.; Duckett, D. R.; Eberwein, D. J.; Knick, V. B.; Lansing, T. J.; McConnell, R. T.; Gilmer, T. M.; Zhang, S. Y.; Robell, K.; Kahana, J. A.; Geske, R. S.; Kleymenova, E. V.; Choudhry, A. E.; Lai, Z.; Leber, J. D.; Minthorn, E. A.; Strum, S. L.; Wood, E. R.; Huang, P. S.; Copeland, R. A.; Kumar, R. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity Cancer Res. 2008, 68, 2366-2374
26. Grimshaw, K. M.; Hunter, L. J.; Yap, T. A.; Heaton, S. P.; Walton, M. I.; Woodhead, S. J.; Fazal, L.; Reule, M.; Davies, T. G.; Seavers, L. C.; Lock, V.; Lyons, J. F.; Thompson, N. T.; Workman, P.; Garrett, M. D. AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth Mol. Cancer Ther. 2010, 9, 1100-1110
27. Lin, K.; Lin, J.; Wu, W.-I.; Ballard, J.; Lee, B. B.; Gloor, S. L.; Vigers, G. P. A.; Morales, T. H.; Friedman, L. S.; Skelton, N. J.; Brandhuber, B. J. An ATP-site on-off switch that restricts phosphatase accessibility of Akt Sci. Signaling 2012, 5, ra37
28. Zaki, M. H.; Nemeth, J. A. CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice Int. J. Cancer 2004, 111, 592-595