Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation

Bioorganic and Medicinal Chemistry Letters

Volumn 23, Issue 13, 2013, Pages 3741-3748

  Furet, Pascal ^a   Guagnano, Vito ^a   Fairhurst, Robin A ^a   Imbach Weese, Patricia ^a   Bruce, Ian ^a   Knapp, Mark ^a   Fritsch, Christine ^a   Blasco, Francesca ^a   Blanz, Joachim ^a   Aichholz, Reiner ^a   Hamon, Jacques ^a   Fabbro, Doriano ^a   Caravatti, Giorgio ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Antitumor agent; PI3K inhibitors

Indexed keywords

NVP BYL 719; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE ALPHA; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CLINICAL EVALUATION; DRUG POTENCY; ENZYME INHIBITION; FEMALE; NONHUMAN; PHYSICAL CHEMISTRY; RAT;

ANIMALS; BIOLOGICAL AVAILABILITY; CELL LINE; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; FEMALE; HUMANS; MICE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHORYLATION; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; THIAZOLES;

EID: 84878836487     PISSN: 0960894X     EISSN: 14643405     Source Type: Journal    
DOI: 10.1016/j.bmcl.2013.05.007     Document Type: Article

References (31)

1. L.C. Cantley Science 296 2002 1655
2. R. Katso, K. Okkenhaug, K. Ahmadi, S. White, J. Timms, and M.D. Waterfield Annu. Rev. Cell Dev. Biol. 17 2001 615
3. Y. Samuels, and K. Ericson Curr. Opin. Oncol. 18 2006 77
4. B.T. Hennessy, D.L. Smith, P.T. Ram, Y. Lu, and G.B. Mills Nat. Rev. Drug Disc. 4 2005 988
5. I. Sansal, and W.R. Sellers J. Clin. Oncol. 22 2004 2954
6. J.Q. Cheng, A.K. Godwin, A. Bellacosa, T. Taguchi, T.F. Franke, T.C. Hamilton, P.N. Tsichlis, and J.R. Testa Proc. Natl. Acad. Sci. U.S.A. 89 1992 9267
7. J.Q. Cheng, B. Ruggeri, W.M. Klein, G. Sonoda, D.A. Altomare, D.K. Watson, and J.R. Testa Proc. Natl. Acad. Sci. U.S.A. 93 1996 3636
8. L. Shayesteh, Y. Lu, W.L. Kuo, R. Baldocchi, T. Godfrey, C. Collins, D. Pinkel, B. Powell, G.B. Mills, and J.W. Gray Nat. Genet. 21 1999 99
9. Y. Samuels, and V.E. Velculescu Cell Cycle 3 2004 1221
10. C. Hartmann, G. Bartels, C. Gehlaar, N. Hotkamp, and A. von Deimling Acta Neuropathol. 109 2005 639
11. V.S. Li, C.W. Wong, T.L. Chan, A.S. Chan, W. Zhao, K.M. Chu, S. So, X. Chen, S.T. Yuen, and S.Y. Leung BMC Cancer 5 2005 29
12. J.W. Lee, Y.H. Soung, S.Y. Kim, H.W. Lee, W.S. Park, S.W. Nam, S.H. Kim, J.Y. Lee, N.J. Yoo, and S.H. Lee Oncogene 24 2005 1477
13. K.E. Bachman, P. Argani, Y. Samuels, N. Silliman, J. Ptak, S. Szabo, H. Konishi, B. Karabas, B.G. Blair, C. Lin, B.A. Peters, V.E. Velculescu, and B.H. Park Cancer Biol. Ther. 3 2004 772
14. I.G. Campbell, S.E. Russell, D.Y. Choong, K.G. Motgomery, M.L. Ciavarella, C.S. Hooi, B.E. Cristiano, R.B. Pearson, and W.A. Phillips Cancer Res. 64 2004 7678
15. D.A. Levine, F. Bogomolniy, C.J. Yee, A. Lash, R.R. Barakat, P.I. Borgen, and J. Boyd Clin. Cancer Res. 11 2005 2875
16. G. Wu, M. Xing, E. Mambo, X. Huang, X. Liu, Z. Guo, A. Chatterjee, D. Goldenberg, S.M. Gollin, S. Sukumar, B. Trink, and D. Sidransky Breast Cancer Res. 7 2005 R609
17. A.J. Folkes, K. Ahmadi, W.K. Alderton, S. Alix, S.J. Baker, G. Box, and I.S. Chuckowree J. Med. Chem. 51 2008 5522
18. B.M. Emerling, and A. Akcakanat Cancer Res. 71 2011 7351
19. M.T. Burger, S. Pecchi, A. Wagman, Z.-J. Ni, M. Knapp, T. Hendrickson, G. Atallah, K. Pfister, Y. Zhang, S. Bartulis, K. Frazier, S. Ng, A. Smith, J. Verhagen, J. Haznedar, K. Huh, E. Iwanowicz, X. Xin, D. Menezes, H. Merritt, I. Lee, M. Wiesmann, S. Kaufman, K. Crawford, M. Chin, D. Bussiere, K. Shoemaker, I. Zaror, S.-M. Maira, and C.F. Voliva ACS Med. Chem. Lett. 2 2011 774
20. S. Yaguchi, Y. Fukui, I. Koshimizu, H. Yoshimi, T. Matsuno, H. Gouda, S. Hirono, K. Yamazaki, and T. Yamori J. Natl. Cancer Inst. 98 2006 545
21. J. Ohwada, H. Ebiike, H. Kawada, M. Tsukazaki, M. Nakamura, T. Miyazaki, K. Morikami, K. Yoshinari, M. Yoshida, O. Kondoh, S. Kuramoto, K. Ogawa, Y. Aoki, and N. Shimma Bioorg. Med. Chem. Lett. 21 2011 1767
22. I. Bruce, M. Akhlaq, G.C. Bloomfield, E. Budd, B. Cox, B. Cuenoud, P. Finan, P. Gedeck, J. Hatto, J.F. Hayler, D. Head, T. Keller, L. Kirman, C. Leblanc, D. Le Grand, C. McCarthy, D. O'Connor, C. Owen, M.S. Oza, G. Pilgrim, N.E. Press, L. Sviridenko, and L. Whitehead Bioorg. Med. Chem. Lett. 22 2012 5445
23. C.-H. Huang, D. Mandelker, O. Schmidt-Kittler, Y. Samuels, V.E. Velculescu, K.W. Kinzler, B. Vogelstein, S.B. Gabelli, and L.M. Amzel Science 318 2007 1744 PDB code 2RD0
24. 2O/GBSA force field. MacroModel: F. Mohamadi, N.G.J. Richards, W.C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang, T. Hendrickson, and W.C. Still J. Comput. Chem. 11 1990 440
25. Z.A. Knight, B. Gonzalez, M.E. Feldman, E.R. Zunder, D.D. Goldenberg, O. Williams, R. Loewith, D. Stokoe, A. Balla, B. Toth, T. Balla, W.A. Weiss, R.L. Williams, and K.M. Shokat Cell 125 2006 733
26. A. Yokooji, T. Okazawa, T. Satoh, M. Miura, and M. Nomura Tetrahedron 59 2003 5685
27. M. Koreeda, and H. Akagi Tetrahedron Lett. 21 1980 1197
28. T.A. Morgan, and B. Ganem Tetrahedron Lett. 21 1980 2773
29. The compounds were tested for their ability to inhibit the phosphorylation of Akt serine 473 in Rat1 cell lines overexpressing activated versions of each class IA PI3K isoform. For a description of these assays see: S.M. Maira Mol. Cancer Ther. 11 2012 317
30. Fritsch, C. et al. in preparation.
31. The details of this X-ray structure determination will be published elsewhere: Knapp, M. et al. in preparation. The coordinates have been deposited with PDB ID code 4JPS.