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

Cheng Mo; Zhang Zhang; Yupeng Li; Minhao Huang; Jian Zou; Jinfeng Luo; Zheng-Chao Tu; Yong Xu; Xiaomei Ren; Ke Ding; Xiaoyun Lu

doi:10.1021/acsmedchemlett.9b00495

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

ACS Med Chem Lett. 2020 Jan 6;11(3):379-384. doi: 10.1021/acsmedchemlett.9b00495. eCollection 2020 Mar 12.

Authors

Cheng Mo^{1

2}, Zhang Zhang¹, Yupeng Li^{2

3}, Minhao Huang², Jian Zou¹, Jinfeng Luo², Zheng-Chao Tu², Yong Xu², Xiaomei Ren¹, Ke Ding¹, Xiaoyun Lu¹

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of PR China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
² Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
³ Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.

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 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.