The design and preliminary structure-activity relationship studies of benzotriazines as potent inhibitors of Abl and Abl-T3151 enzymes

被引：27

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 21期

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.

引用

页码：5812 / 5818

页数：7

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