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Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase

文献类型：期刊论文

作者Zhan, Zhengsheng1; Ji, Yinchun2; Su, Haixia3,4; Fang, Chen1,5; Peng, Xia2; Liu, Qiufeng3,4; Dai, Yang2; Lin, Dongze2; Xu, Yechun3,4,6,7; Ai, Jing2,6,8
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2022-12-16
页码15
ISSN号0022-2623
DOI10.1021/acs.jmedchem.2c00962
通讯作者Xu, Yechun(ycxu@simm.ac.cn) ; Ai, Jing(jai@simm.ac.cn) ; Duan, Wenhu(whduan@simm.ac.cn)
英文摘要Receptor tyrosine kinase AXL exerts pivotal roles in cancer cell survival, metastasis, and drug resistance. Pharmacologic or genetic targeting of the aberrant AXL signaling has proven preferable antitumor efficacies in both preclinical and clinical studies, which highlights AXL as an attractive antitumor drug target. By conformational restriction of the anilinopyrimidine 10e and systematic structure-activity relationship (SAR) exploration, we discovered 10H-benzo[b]pyrido[2,3-e][1,4]oxazine 16j as a potent and orally bioavailable AXL inhibitor. As a type II AXL inhibitor, compound 16j displayed about 15-fold selectivity for AXL over its highly homologous kinase c-Met. And it significantly blocked cellular AXL signaling, inhibited AXL-mediated cell proliferation, and impaired growth arrest-specific protein 6 (Gas6)/AXL-stimulated cell migration and invasion. Moreover, 16j exhibited significant antitumor efficacy in AXL-driven xenograft model at a well-tolerant dosage, causing tumor stasis or regression.
WOS关键词CELLS
资助项目Shanghai Institute of Materia Medica[CASIMM0120215010] ; Lingang Laboratory[LG202103-02-08] ; Science and Technology Commission of Shanghai Municipality[21ZR1475700] ; Youth Innovation Promotion Association of CAS[2018324] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; National Natural Science Foundation of China[21702220] ; National Natural Science Foundation of China[21877122] ; National Natural Science Foundation of China[82173834]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000903311600001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/304210]  
专题新药研究国家重点实验室
通讯作者Xu, Yechun; Ai, Jing; Duan, Wenhu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Small Mol Drug Res Ctr, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
7.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
8.Hangzhou Inst Adv Study UCAS, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Zhan, Zhengsheng,Ji, Yinchun,Su, Haixia,et al. Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022:15.
APA Zhan, Zhengsheng.,Ji, Yinchun.,Su, Haixia.,Fang, Chen.,Peng, Xia.,...&Duan, Wenhu.(2022).Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase.JOURNAL OF MEDICINAL CHEMISTRY,15.
MLA Zhan, Zhengsheng,et al."Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase".JOURNAL OF MEDICINAL CHEMISTRY (2022):15.

入库方式： OAI收割

来源：上海药物研究所

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