Discovery of novel Bcr-AblT3151 inhibitors with flexible linker. Part 1: Confirmation optimization of phenyl-1H-indazol-3-amine as hinge binding moiety
Discovery of novel Bcr-AblT3151 inhibitors with flexible linker. Part 1: Confirmation optimization of phenyl-1H-indazol-3-amine as hinge binding moiety
复制标题
发现具有柔性接头的新型 Bcr-Abl(T315I) 抑制剂。
DOI：
10.1016/j.ejmech.2019.05.091
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发表时间：
2019-09-15
影响因子：
6.7
通讯作者：
Zhang, Jie
中科院分区：
文献类型：
--
作者：
Pan, Xiaoyan;Liang, Liyuan;Zhang, Jie
As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-Abl(wT) and Bcr-Abl(T3151) in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-Abl(wT) and Bcr-Abl(T3151) kinases with IC50 of 0.043 mu M and 0.17 mu M, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC50 of 1.65 mu M and 5.42 mu M, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization. (C) 2019 Elsevier Masson SAS. All rights reserved.
