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Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors

文献类型：期刊论文

作者Wang, Yuming1,3; Li, Lijun2,3; Fan, Jun1,3; Dai, Yang2,3; Jiang, Alan2,3; Geng, Meiyu2,3; Ai, Jing2,3; Duan, Wenhu1,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2018-10-25
卷号61期号:20页码:9085-9104
ISSN号0022-2623
DOI10.1021/acs.jmedchem.7b01843
文献子类Article
英文摘要Fibroblast growth factor receptors (FGFRI-4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies, 9g displayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9g to FGFR.
WOS关键词TYROSINE KINASE INHIBITORS ; SELECTIVE INHIBITOR ; CH5183284/DEBIO 1347 ; OVERCOME RESISTANCE ; COVALENT INHIBITORS ; BREAST-CANCER ; SOLID TUMORS ; DESIGN ; MODELS ; FAMILY
资助项目National Natural Science Foundation[81573271] ; National Natural Science Foundation[81773762] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020303] ; Shanghai Science and Technology Commission[15431901300]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000448754900007
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/279527]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物化学研究室
通讯作者Ai, Jing; Duan, Wenhu
作者单位1.Chinese Acad Sci, SIMM, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yuming,Li, Lijun,Fan, Jun,et al. Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(20):9085-9104.
APA Wang, Yuming.,Li, Lijun.,Fan, Jun.,Dai, Yang.,Jiang, Alan.,...&Duan, Wenhu.(2018).Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,61(20),9085-9104.
MLA Wang, Yuming,et al."Discovery of Potent Irreversible Pan-Fibroblast Growth Factor Receptor (FGFR) Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 61.20(2018):9085-9104.

入库方式： OAI收割

来源：上海药物研究所

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