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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

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posted on 2016-08-22, 00:00 authored by Binhua Li, Aoli Wang, Juan Liu, Ziping Qi, Xiaochuan Liu, Kailin Yu, Hong Wu, Cheng Chen, Chen Hu, Wenchao Wang, Jiaxin Wu, Zhenquan Hu, Ling Ye, Fengming Zou, Feiyang Liu, Beilei Wang, Li Wang, Tao Ren, Shaojuan Zhang, Mingfeng Bai, Shanchun Zhang, Jing Liu, Qingsong Liu
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 strong antiproliferative effect against GISTs cancer cell lines GIST-T1 (cKIT wt, GI50 = 4 nM) and GIST-5R (cKIT T670I, GI50 = 26 nM). In the cellular context it strongly inhibited c-KIT mediated signaling pathways and induced apoptosis. In the BaF3-TEL-cKIT-T670I isogenic cell inoculated xenograft mouse model, 35 exhibited dose dependent tumor growth suppression efficacy and 100 mg/kg dosage provided 47.7% tumor growth inhibition (TGI) without obvious toxicity. We believe compound 35 would be a good pharmacological tool for exploration of the cKIT-T670I mutant mediated pathology in GISTs.

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