3'-(咪唑并[1,2 -]吡嗪 - 3 - 基)-[1,1'-联苯]-3 - 羧酰胺作为选择性DDR1抑制剂的设计与优化
Design and Optimization of 3'-(Imidazo[1,2-]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as Selective DDR1 Inhibitors.
作者信息
Mo Cheng, Zhang Zhang, Li Yupeng, Huang Minhao, Zou Jian, Luo Jinfeng, Tu Zheng-Chao, Xu Yong, Ren Xiaomei, Ding Ke, Lu Xiaoyun
机构信息
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.
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
出版信息
ACS Med Chem Lett. 2020 Jan 6;11(3):379-384. doi: 10.1021/acsmedchemlett.9b00495. eCollection 2020 Mar 12.
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-]pyrazin-3-yl)-[1,1'-biphenyl]-3-carboxamides as novel selective DDR1 inhibitors. Among these, compound potently inhibited DDR1 with an IC of 23.8 nM, while it showed less inhibitory activity against DDR2 (IC = 1740 nM) and negligible activities against Bcr-Abl (IC > 10 μM) and c-Kit (IC > 10 μM). 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.
摘要
DDR1被认为是癌症治疗的一个有前景的靶点，与其他激酶相比，针对DDR1的选择性抑制剂可能被视为有前景的治疗药物。在此，我们鉴定出一系列3'-(咪唑并[1,2 -]吡嗪 - 3 - 基)-[1,1'-联苯]-3 - 羧酰胺作为新型选择性DDR1抑制剂。其中，化合物对DDR1具有强效抑制作用，IC为23.8 nM，而对DDR2的抑制活性较低（IC = 1740 nM），对Bcr - Abl（IC > 10 μM）和c - Kit（IC > 10 μM）的活性可忽略不计。在具有468种激酶的KINOMEscan筛选平台中也表现出优异的选择性。该化合物剂量依赖性地抑制NSCLC细胞的肿瘤发生、迁移和侵袭。总体而言，这些研究支持其在NSCLC治疗中的潜在应用。
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