Structure-based drug discovery of novel fusedpyrazolone carboxamide derivatives as potent and selective AXL inhibitors  

作　　者：Feifei Fang Yang Dai Hao Wang Yinchun Ji Xuewu Liang Xia Peng Jiyuan Li Yangrong Zhao Chunpu Li Danyi Wangh Yazhou Li Dong Zhang Dan Zhang Meiyu Geng Hong Liu Jing Ai Yu Zhou 

机构地区：[1]Lingang Laboratory,Shanghai 200031,China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]Drug Discovery&Development Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [4]University of Chinese Academy of Sciences,Beijing 100049,China [5]Shandong Laboratory of Yantai Drug Discovery,Bohai Rim Advanced Research Institute for Drug Discovery,Yantai 264117,China [6]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou 310024,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4918-4933,共16页药学学报（英文版）

基　　金：supported by the Natural Science Foundation of China for Innovation Research Group(81821005);the National Natural Science Foundation of China(21977106 and 82173834);the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning(2020CXJQ02);the Shanghai Post-doctoral Excellence Program(2022231,China);the Shanghai Sail Program(22YF1460700,China);Lingang Laboratory(LG202103-02-07,China);Lingang Laboratory(LGGG-202204-02,China).

摘　　要：a novel and promising antitumor target,AXL plays an important role in tumor growth,metastasis,immunosuppression and drug resistance of various malignancies,which has attracted extensive research interest in recent years.In this study,by employing the structure-based drug design and bioisosterism strategies,we designed and synthesized in total 54 novel AXL inhibitors featuring a fusedpyrazolone carboxamide scaffold,of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions.Notably,compound 59 showed a desirable AXL kinase inhibitory activity(IC_(50):3.5 nmol/L)as well as good kinase selectivity,and it effectively blocked the cellular AXL signaling.In turn,compound 59 could potently inhibit BaF3/TEL-AXL cell viability(IC_(50):1.5 nmol/L)and significantly suppress GAS6/AXL-mediated cancer cell invasion,migration and wound healing at the nanomolar level.More importantly,compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency,in which we observed significant AXL phosphorylation suppression,and its antitumor efficacy at 20 mg/kg(qd)was comparable to that of BGB324 at 50 mg/kg(bid),the most advanced AXL inhibitor.Taken together,this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.

关 键 词：Potential AXL inhibitor Antitumor activity Structure-based drug design Fused-pyrazolone carboxamide 

分 类 号：R914[医药卫生—药物化学]