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

文献类型：期刊论文

作者Fang, Feifei6; Dai, Yang5; Wang, Hao3,4; Ji, Yinchun5; Liang, Xuewu3,5; Peng, Xia5; Li, Jiyuan5; Zhao, Yangrong5; Li, Chunpu3,5; Wang, Danyi3,5
刊名ACTA PHARMACEUTICA SINICA B
出版日期2023-12-01
卷号13期号:12页码:4918-4933
ISSN号2211-3835
关键词derivatives Antitumor drug development Potential AXL inhibitor Antitumor activity Structure-based drug design Fused-pyrazolone carboxamide
DOI10.1016/j.apsb.2023.10.002
通讯作者Liu, Hong(hliu@simm.ac.cn) ; Ai, Jing(jai@simm.ac.cn) ; Zhou, Yu(zhouyu@simm.ac.cn)
英文摘要As 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 exten-sive research interest in recent years. In this study, by employing the structure-based drug design and bio-isosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone 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 inhib-itory activity (IC50: 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 (IC50: 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. (c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词RECEPTOR TYROSINE KINASE ; SMALL-MOLECULE INHIBITOR ; PRIVILEGED SCAFFOLD ; BEMCENTINIB BGB324 ; ADVERSE PROGNOSIS ; GROWTH-ARREST ; GAS6/AXL AXIS ; TARGETING AXL ; PHASE-II ; CANCER
资助项目Natural Science Foundation of China for Innovation Research Group[81821005] ; National Natural Science Foundation of China[21977106] ; National Natural Science Foundation of China[82173834] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] ; Shanghai Post-doctoral Excellence Program[2022231] ; Shanghai Sail Program[22YF1460700] ; Lingang Laboratory[LG202103-02-07] ; Lingang Laboratory[LG-GG-202204-02]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号WOS:001125750300001
源URL[http://119.78.100.183/handle/2S10ELR8/308353]  
专题新药研究国家重点实验室
通讯作者Liu, Hong; Ai, Jing; Zhou, Yu
作者单位1.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Dev Ctr, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
6.Lingang Lab, Shanghai 200031, Peoples R China
推荐引用方式
GB/T 7714		 Fang, Feifei,Dai, Yang,Wang, Hao,et al. Structure-based drug discovery of novel fused- pyrazolone carboxamide derivatives as potent and selective AXL inhibitors[J]. ACTA PHARMACEUTICA SINICA B,2023,13(12):4918-4933.
APA Fang, Feifei.,Dai, Yang.,Wang, Hao.,Ji, Yinchun.,Liang, Xuewu.,...&Zhou, Yu.(2023).Structure-based drug discovery of novel fused- pyrazolone carboxamide derivatives as potent and selective AXL inhibitors.ACTA PHARMACEUTICA SINICA B,13(12),4918-4933.
MLA Fang, Feifei,et al."Structure-based drug discovery of novel fused- pyrazolone carboxamide derivatives as potent and selective AXL inhibitors".ACTA PHARMACEUTICA SINICA B 13.12(2023):4918-4933.

入库方式： OAI收割

来源：上海药物研究所

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