American Chemical Society
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Design and Optimization of 3′-(Imidazo[1,2‑a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors

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journal contribution
posted on 2020-01-09, 17:47 authored by Cheng Mo, Zhang Zhang, Yupeng Li, Minhao Huang, Jian Zou, Jinfeng Luo, Zheng-Chao Tu, Yong Xu, Xiaomei Ren, Ke Ding, Xiaoyun Lu
DDR1 is considered as a promising target for cancer therapy, and selective inhibitors against DDR1 over other kinases may be considered as promising therapeutic agents. Herein, we have identified a series of 3′-(imidazo­[1,2-a]­pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound 8v potently inhibited DDR1 with an IC50 of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC50 = 1740 nM) and negligible activities against Bcr-Abl (IC50 > 10 μM) and c-Kit (IC50 > 10 μM). 8v also exhibited excellent selectivity in a KINOMEscan screening platform with 468 kinases. This compound dose-dependently suppressed NSCLC cell tumorigenicity, migration, and invasion. Collectively, these studies support its potential application for treatment of NSCLC.