Journal article

Discovery of (E)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thio)propanamide (CHMFL-ABL-121) as a highly potent ABL kinase inhibitor capable of overcoming a variety of ABL mutants including T315I for chronic myeloid leukemia.

Xuesong Liu, Beilei Wang, Cheng Chen, Zongru Jiang, Chen Hu, Hong Wu, Yicong Zhang, Xiaochuan Liu, Wenliang Wang, Junjie Wang, Zhenquan Hu, Aoli Wang, Tao Huang, Qingwang Liu, Wei Wang, Li Wang, Wenchao Wang, Tao Ren, Lili Li, Ruixiang Xia Show all

European Journal of Medicinal Chemistry | Published : 2018

Abstract

There is still a great demand in the clinic for the drugs which can overcome a variety of imatinib resistant ABL mutants. Starting from a type I inhibitor axitinib, which has been reported to overcome ABL-T315I mutant induced resistance, through a structure guided drug design approach and binding mode switch strategy, we have discovered a novel type II ABL inhibitor 24 (CHMFL-ABL-121), which significantly improved the inhibitory activity against ABL wt and a broad spectrum of mutants including the most prevalent imatinib-resistant gatekeeper mutant T315I. 24 exhibited IC50 values of 2 nM and 0.2 nM against purified inactive ABL wt and T315I kinase protein respectively and inhibited the proli..

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University of Melbourne Researchers