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The design and preliminary structure-activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T3151 enzymes
被引:26
作者:
Cao, Jianguo
Fine, Richard
Gritzen, Colleen
Hood, John
Kang, Xinshan
Klebansky, Boris
Lohse, Dan
Mak, Chi Ching
McPherson, Andrew
Noronha, Glenn
Palankl, Moorthy S. S.
Pathak, Ved P.
Renick, Joel
Solla, Richard
Zenga, Binqi
Zhu, Hong
机构:
[1] TargeGen Inc, San Diego, CA 92121 USA
[2] BioPredict Inc, Oradell, NJ 07649 USA
关键词:
Abl inhibitor;
Abl-T3151;
Bcr-Abl;
cancer;
kinase inhibitor;
benzotriazines;
CML;
chronic myeloid leukemia;
D O I:
10.1016/j.bmcl.2007.08.043
中图分类号:
R914 [药物化学];
学科分类号:
100701 ;
摘要:
We describe the design, synthesis and structure-activity relationship studies in optimizing a series of benzotriazine compounds as potent inhibitors of both Abl and Abl-T315I enzymes. The design includes targeting of an acid functional residue on the alpha C-helix that is available only upon kinase activation. This designed interaction provides an advantage in overcoming the challenges arising from the T315I mutation of Abl and transforms poor (ca. 10 mu M) inhibitors into those with low nM potency. (c) 2007 Elsevier Ltd. All rights reserved.
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页码:5812 / 5818
页数:7
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