Design, synthesis, and biological evaluation of 3-(1H-1,2,3-triazol-1-yl) benzamide derivatives as potent pan Bcr-Abl inhibitors including the threonine315←isoleucine315 mutant

Yupeng Li, Mengjie Shen, Zhang Zhang, Jinfeng Luo, Xiaofen Pan, Xiaoyun Lu, Huoyou Long, Donghai Wen, Fengxiang Zhang, Fang Leng, Yingjun Li, Zhengchao Tu, Xiaomei Ren, Ke Ding

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26 Scopus citations

Abstract

A series of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives were designed and synthesized as new Bcr-Abl inhibitors by using combinational strategies of bioisosteric replacement, scaffold hopping, and conformational constraint. The compounds displayed significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I and p-loop mutations, which are associated with disease progression in CML. The most potent compounds 6q and 6qo strongly inhibited the kinase activities of Bcr-AblWT and Bcr-AblT315I with IC50 values of 0.60, 0.36 and 1.12, 0.98 nM, respectively. They also potently suppressed the proliferation of K562, KU812 human CML cells, and a panel of murine Ba/F3 cells ectopically expressing either Bcr-AblWT or any of a panel of other Bcr-Abl mutants that have been shown to contribute to clinical acquired resistance, including Bcr-AblT315I, with IC50 values in low nanomolar ranges. These compounds may serve as lead compounds for further development of new Bcr-Abl inhibitors capable of overcoming clinical acquired resistance against imatinib.

Original languageEnglish (US)
Pages (from-to)10033-10046
Number of pages14
JournalJournal of Medicinal Chemistry
Volume55
Issue number22
DOIs
StatePublished - Nov 26 2012
Externally publishedYes

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