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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.

ABSTRACT: 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 ?M) and c-Kit (IC50 > 10 ?M). 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.

SUBMITTER: Mo C 

PROVIDER: S-EPMC7074218 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Design and Optimization of 3'-(Imidazo[1,2-<i>a</i>]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors.

Mo Cheng C   Zhang Zhang Z   Li Yupeng Y   Huang Minhao M   Zou Jian J   Luo Jinfeng J   Tu Zheng-Chao ZC   Xu Yong Y   Ren Xiaomei X   Ding Ke K   Lu Xiaoyun X  

ACS medicinal chemistry letters 20200106 3

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-<i>a</i>]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound <b>8v</b> potently inhibited DDR1 with an IC<sub>50</sub> of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC<sub>50</sub> = 1740 nM) and negligib  ...[more]

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