Open AccessDesign and Optimization of 3′-(Imidazo[1,2-a]pyrazin-3-yl)-[1,1′-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors
Author(s) -
MingJen Cheng,
Zhang Zhang,
Yupeng Li,
Ming Huang,
Jian Zou,
Jinfeng Luo,
Zhengchao Tu,
Yong Xu,
Xiaomei Ren,
Ke Ding,
Xiaoyun Lu
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00495
Subject(s) - ic50 , kinase , chemistry , biphenyl , ddr1 , small molecule , pharmacology , structure–activity relationship , cancer research , combinatorial chemistry , biochemistry , receptor tyrosine kinase , biology , in vitro , organic chemistry
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 IC 50 of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC 50 = 1740 nM) and negligible activities against Bcr-Abl (IC 50 > 10 μM) and c-Kit (IC 50 > 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.