A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl
- A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl
- 최환근; 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 Mestan; Nathanael S. Gray; 심태보
- Issue Date
- Journal of medicinal chemistry
- VOL 53, NO 15, 5439-5448
- 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.
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