Article
Discovery of N-((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)propionamide (CHMFL-KIT-8140) as a Highly Potent Type II Inhibitor Capable of Inhibiting the T670I "Gatekeeper" Mutant of cKIT Kinase.
Journal of medicinal chemistry - 22 Sept 2016
Li Binhua, Wang Aoli, Liu Juan, Qi Ziping, Liu Xiaochuan, Yu Kailin, Wu Hong, Chen Cheng, Hu Chen, Wang Wenchao, Wu Jiaxin, Hu Zhenquan, Ye Ling, Zou Fengming, Liu Feiyang, Wang Beilei, Wang Li, Ren Tao, Zhang Shaojuan, Bai Mingfeng, Zhang Shanchun, Liu Jing, Liu Qingsong
Abstract excerpt
cKIT kinase inhibitors, e.g., imatinib, could induce drug-acquired mutations such as cKIT T670I that rendered drug resistance after chronic treatment. Through a type II kinase inhibitor design approach we discovered a highly potent type II cKIT kinase inhibitor compound 35 (CHMFL-KIT-8140), which potently inhibited both cKIT wt (IC50 = 33 nM) and cKIT gatekeeper T670I mutant (IC50 = 99 nM). Compound 35 displayed...
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