The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer

Journal of Medicinal Chemistry

Volumn 51, Issue 18, 2008, Pages 5522-5532

  Folkes, Adrian J ^a   Ahmadi, Khatereh ^a   Alderton, Wendy K ^a   Alix, Sonia ^b   Baker, Stewart J ^a   Box, Gary ^b   Chuckowree, Irina S ^a   Clarke, Paul A ^b   Depledge, Paul ^a   Eccles, Suzanne A ^b   Friedman, Lori S ^c   Hayes, Angela ^b   Hancox, Timothy C ^a   Kugendradas, Arumugam ^a   Lensun, Letitia ^a   Moore, Pauline ^a   Olivero, Alan G ^c   Pang, Jodie ^c   Patel, Sonal ^a   Pergl Wilson, Giles H ^a   Raynaud, Florence I ^b   Robson, Anthony ^a   Saghir, Nahid ^a   Salphati, Laurent ^c   Sohal, Sukhjit ^a   Ultsch, Mark H ^c   Valenti, Melanie ^b   Wallweber, Heidi J A ^c   Nan, Chi Wan ^a   Wiesmann, Christian ^c   Workman, Paul ^b   Zhyvoloup, Alexander ^a   Zvelebil, Marketa J ^d   Shuttleworth, Stephen J ^a   more..

^a Piramed Pharma   (United Kingdom)

^b IMPERIAL CANCER RESEARCH FUND   (United Kingdom)

^c GENENTECH INC   (United States)

^d INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 (1H INDAZOL 4 YL) 6 (4 METHANESULFONYLPIPERAZIN 1 YLMETHYL) 4 MORPHOLIN 4 YLTHIENO[3,2 D]PYRIMIDINE; 3 [6 (4 METHYLPIPERAZIN 1 YLMETHYL) 4 MORPHOLIN 4 YLTHIENO[3,2 D]PYRIMIDIN 2 YL]PHENOL; GDC 0941; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; PROTEIN P110; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BIOLOGICAL ACTIVITY; CANCER THERAPY; CELL LINE; CELL PROLIFERATION; CONTROLLED STUDY; DEREGULATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG HALF LIFE; DRUG INHIBITION; DRUG METABOLISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; FEMALE; GLUCURONIDATION; GROWTH INHIBITION; HUMAN; HUMAN CELL; MALE; MOUSE; NONHUMAN; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; TUMOR GROWTH;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ADMINISTRATION, ORAL; ANTINEOPLASTIC AGENTS; BIOLOGICAL AVAILABILITY; CELL LINE, TUMOR; DRUG SCREENING ASSAYS, ANTITUMOR; ENZYME INHIBITORS; HUMANS; INDAZOLES; MAGNETIC RESONANCE SPECTROSCOPY; MOLECULAR STRUCTURE; NEOPLASMS; SULFONAMIDES;

EID: 52449106253     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800295d     Document Type: Article

References (37)

1. Vanhaesebroeck, B.; Leevers, S. J.; Ahmadi, K.; Timms, J.; Katso, R.; Driscoll, P. C.; Woscholski, R.; Parker, P. J.; Waterfield, M. D. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 2001, 70, 535-602.
2. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 2002, 296, 1655-1657.
3. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489-501.
4. Shayesteh, L.; Kuo, W. L.; Baldocchi, R.; Godfrey, T.; Collins, C.; Pinkel, D.; Powell, B.; Mills, G. B.; Gray, J. W. PIK3CA is implicated as an oncogene in ovarian cancer. Nat. Genet. 1999, 21, 99-102.
5. Samuels, Y.; Wang, Z.; Bardelli, A.; Silliman, N.; Ptak, J.; Szabo, S.; Yan, H.; Gazdar, A.; Powell, S. M.; Riggins, G. J.; Willson, J. K.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004, 30, 554.
6. Parsons, D. W.; Wang, T. L.; Samuels, Y.; Bardelli, A.; Cummins, J. M.; DeLong, L.; Silliman, N.; Ptak, J.; Szabo, S.; Willson, J. K.; Markowitz, S.; Kinzler, K. W.; Vogelstein, B.; Lengauer, C.; Velculescu, V. E. Colorectal cancer: mutations in a signalling pathway. Nature 2005, 436, 792.
7. Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discovery 2005, 4, 98-104.
8. Sulis, M. L.; Parsons, R. PTEN: from pathology to biology. Trends Cell. Biol. 2003, 13, 478-483.
9. Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S. I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; Bigner, S. H.; Giovanella, B. C.; Ittmann, M.; Tycko, B.; Hibshoosh, H.; Wigler, M. H.; Parsons, R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275, 1943-1947.
10. She, Q. B.; Solit, D.; Basso, A.; Moasser, M. M. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin. Cancer Res. 2003, 9, 4340-4346.
11. Berns, K.; Horlings, H. M.; Hennessy, B. T.; Madiredjo, M.; Hijmans, E. M.; Beelen, K.; Linn, S. C.; Gonzalez-Angulo, A. M.; Stemke-Hale, K.; Hauptmann, M.; Beijersbergen, R. L.; Mills, G. B.; van de Vijver, M. J.; Bernards, R. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 2007, 12, 395-402.
12. Nagata, Y.; Lan, K. H.; Zhou, X.; Tan, M.; Esteva, F. J.; Sahin, A. A.; Klos, K. S.; Li, P.; Monia, B. P.; Nguyen, N. T.; Hortobagyi, G. N.; Hung, M. C.; Yu, D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004, 6, 117-127.
13. Wee, S.; Lengauer, C.; Wiederschain, D. Class IA phospoinositide 3-kinase isoforms and human tumorigenesis: implications for cancer drug discovery and development. Curr. Opin. Oncol. 2008, 20, 77-82.
14. Drees, B. E.; Mills, G. B.; Rommel, C.; Prestwich, G. D. Therapeutic potential of phospoinositide 3-kinase inhibitors. Expert Opin. Ther. Patents 2004, 14, 703-732.
15. Schultz, R. M.; Merriman, R. L.; Andis, S. L.; Bonjouklian, R.; Grindley, G. B.; Rutherford, P. G.; Gallegos, A.; Massey, K.; Powis, G. In vitro and in vivo antitumor activity of the phosphatidylinositol-3-kinase inhibitor, wortmannin. Anticancer Res. 1995, 15, 1135-1139.
16. Norman, B. H.; Shih, C.; Toth, J. E.; Ray, J. E.; Dodge, J. A.; Johnson, D. W.; Rutherford, P. G.; Schultz, R. M.; Worzalla, J. F.; Vlahos, C. J. Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs. J. Med. Chem. 1996, 39, 1106-1111.
17. Vlahos, C. J.; Matter, W. F.; Hui, K. Y.; Brown, R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4 H-1-benzopyran-4-one (LY294002). J. Biol. Chem. 1994, 269, 5241-5248.
18. Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Okada, M.; Ohta, M.; Tsukamoto, S.; Parker, P.; Workman, P.; Waterfield, M. Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110α inhibitors. Biorg. Med. Chem. 2006, 14, 6847-6858.
19. Hayakawa, M.; Kaizawa, H.; Moritomo, H.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.; Raynaud, F.; Workman, P.; Waterfield, M.; Parker, P. Synthesis and biological evaluation of pyrido[3′,2′: 4,5]furo[3,2-d]pyrimidine derivatives as novel PI3 kinase p110α inhibitors. Biorg. Med. Chem. Lett. 2007, 17, 2438-2442.
20. Raynaud, F.; Eccles, S.; Clarke, P.; Hayes, A.; Nutley, B.; Alix, S.; Henley, A.; Di-Stefano, F.; Ahmad, Z.; Guillard, S.; Bjerke, L.; Kelland, L.; Valenti, M.; Patterson, L.; Gowan, S.; de Haven Brandon, A.; Hayakawa, M.; Kaizawa, H.; Koizumi, T.; Ohishi, T.; Patel, S.; Saghir, N.; Parker, P.; Waterfield, M.; Workman, P. Pharmacological Characterization of a Potent Inhibitor of Class I Phosphatidylinositide 3-Kinases. Cancer Res. 2007, 67, 5840-5850.
21. Fan, Q. W.; Knight, Z. A.; Goldenberg, D. D.; Yu, W.; Mostov, K. E.; Stokoe, D.; Shokat, K. M.; Weiss, W. A. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioblastoma. Cancer Cell 2006, 9, 341-349.
22. Woitun, E.; Ohnacker, G.; Narr, B.; Horch, U.; Kadatz, R. U.S. Patent 3763156, 1973.
23. Turbidimetric (kinetic) solubility measurements were conducted at Cyprotex using the Cloe screen. Measurements were made at pH 7.4 using 10 mM of compound in DMSO as the initial stock solution.
24. Walker, E. H.; Pacold, M. E.; Perisic, O.; Stephens, L.; Hawkins, P. T.; Wymann, M. P.; Williams, R. L. Structural Determinants of Phosphoinositide 3-Kinase Inhibition by Wortmannin, LY294002, Quercetin, Myricetin, and Staurosporine. Mol. Cell 2000, 6, 909-919.
25. Pirola, L.; Zvelebil, M. J.; Bulgarelli-Leva, G.; Van Obberghen, E.; Waterfield, M. D.; Wymann, M. P. Activation loop sequences confer substrate specificity to phosphoinositide 3-kinase alpha (PI3Kalpha). Functions of lipid kinase-deficient PI3Kalpha in signaling. J. Biol. Chem. 2001, 276, 21544.
26. Zvelebil, M. J.; Baum, J. O. In Understanding Bioinformatics; Garland Publishing Inc.: New York, 2007.
27. 24-29 and we concluded that the cff forcefield, in general, provided the best binding orientations. The definition of the binding site was a crucial step, and while in our docking analyses, we mainly employed the cff forcefield, and the number of highest scores along with the consensus score was used as a guide to an optimum ligand fit.
28. Parts b and c of Figure 2 were generated using PyMOL, see: DeLano, W. L. The PyMOL Molecular Graphics System. DeLano Scientific: San Carlos, CA, 2002.
29. Walker, E. H.; Perisic, O.; Reid, C.; Stephens, L.; Williams, R. L. Nature 1999, 402, 313.
30. Samuels, Y.; Diaz, L. A.; Schmidt-Kittler, O.; Cummins, J. M.; DeLong, L.; Cheong, I.; Rago, C.; Huso, D. L.; Lengauer, C.; Kinzler, K. W.; Vogelstein, B.; Velculescu, V. E. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005, 7, 561-573.
31. Kang, S.; Bader, A. G.; Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 802-807.
32. Davies, S. P.; Reddy, H.; Caivano, M.; Cohen, P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem. J. 2000, 351, 95-105.
33. CYP450 inhibition was measured using a fluorescence based assay at BioFocus DPI.
34. CYP450 induction was measured using fresh human hepatocytes in the Cloe Screen at Cyprotex.
35. Measured using a whole cell patch clamp assay at BioFocus DPI.
36. Workman, P.; Twentyman, P.; Balkwill, F. United Kingdom Coordinating Committee on Cancer Research Guidelines for the Welfare of Animals in Experimental Neoplasia. 2nd Ed. Cancer 1998, 77, 1-10.
37. Eccles, S. A.; Court, W. J.; Box, G. A.; Dean, C. J.; Melton, R. G.; Springer, C. J. Regression of established breast carcinoma xenografts with antibody-directed enzyme prodrug therapy against c-erbB2 p185. Cancer Res. 1994, 54, 5171-5177.