| Literature DB >> 20604564 |
Hwan Geun Choi1, Pingda Ren, Francisco Adrian, Fangxian Sun, Hyun Soo Lee, Xia Wang, Qiang Ding, Guobao Zhang, Yongping Xie, Jianming Zhang, Yi Liu, Tove Tuntland, Markus Warmuth, Paul W Manley, Jürgen Mestan, Nathanael S Gray, Taebo Sim.
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(1H)-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, E255K, E255V, F317L, and M351T in biochemical and cellular assays. In addition, compound 2 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. Compound 2 is among the first type-II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design the third generation Bcr-Abl kinase inhibitors.Entities:
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Year: 2010 PMID： 20604564 PMCID： PMC4134510 DOI： 10.1021/jm901808w
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446