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

Title
A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” Mutant of Bcr-Abl
Authors
최환근Pingda RenFrancisco AdrianFangxian SunHyun Soo LeeXia WangQiang DingGuobao ZhangYongping XieJianming ZhangYi LiuTove TuntlandMarkus WarmuthPaul W. ManleyJrgen MestanNathanael S. Gray심태보
Issue Date
2010-08
Publisher
Journal of medicinal chemistry
Citation
VOL 53, NO 15, 5439-5448
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.
URI
http://pubs.kist.re.kr/handle/201004/38286
ISSN
0022-2623
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