A type-II kinase inhibitor capable of inhibiting the T315I “gatekeeper” mutant of Bcr-Abl

…, F Adrian, F Sun, HS Lee, X Wang, Q Ding…

Index: Choi, Hwan Geun; Ren, Pingda; Adrian, Francisco; Sun, Fangxian; Lee, Hyun Soo; Wang, Xia; Ding, Qiang; Zhang, Guobao; Xie, Yongping; Zhang, Jianming; Liu, Yi; Tuntland, Tove; Warmuth, Markus; Manley, Paul W.; Mestan, Juergen; Gray, Nathanael S.; Sim, Taebo Journal of Medicinal Chemistry, 2010 , vol. 53, # 15 p. 5439 - 5448

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Citation Number: 46

Abstract

The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I “gatekeeper” mutation. Here we describe a type-II T315I inhibitor 2 (GNF-7), based upon a 3, 4-dihydropyrimido [4, 5-d] pyrimidin-2 (1 H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr- Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, Q252H, Y253H, ...