A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl

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• 作者：Hwan Geun Choi ; 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 ; Jrgen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 12, 2010
• 年：2010
• 卷：53
• 期：15
• 页码：5439-5448
• 全文大小：949K
• 年卷期：v.53,no.15(August 12, 2010)
• ISSN：1520-4804

文摘

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.