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Discovery of 3-(5 '-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation

文献类型：期刊论文

作者Yan, Wei2; Wang, Xinyi3,6; Dai, Yang3; Zhao, Bin4; Yang, Xinying3; Fan, Jun4; Gao, Yinglei3; Meng, Fanwang1,5; Wang, Yuming4; Luo, Cheng
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2016-07-28
卷号59期号:14页码:6690-6708
ISSN号0022-2623
DOI10.1021/acs.jmedchem.6b00056
文献子类Article
英文摘要Fibroblast growth factor receptor (FGFR) represents an attractive oncology target for cancer therapy in view of its critical role in promoting cancer formation and progression, as well as causing resistance to approved therapies. In this article, we describe the identification of the potent pan-FGFR inhibitor (R)-21c (FGFR1-4 IC50 values of 0.9, 2.0, 2.0, and 6.1 nM, respectively). Compound (R)-21c exhibited excellent in vitro inhibitory activity against a panel of FGFR-amplified cell lines. Western blot analysis demonstrated that (R)-21c suppressed FGF/FGFR and downstream signaling pathways at nanomolar concentrations. Moreover, (R)-21c provided nearly complete inhibition of tumor growth (96.9% TGI) in NCI-H1581 (FGFR1-amplified) xenograft mice model at the dose of 10 mg/kg/qd via oral administration.
WOS关键词TYROSINE KINASE ; SELECTIVE INHIBITOR ; HEPATOCELLULAR-CARCINOMA ; ANTIANGIOGENIC THERAPY ; CELL CARCINOMA ; BREAST-CANCER ; RESISTANCE ; FGFR ; ANGIOGENESIS ; EXPRESSION
资助项目National Natural Science Foundation of China[81273365] ; National Natural Science Foundation of China[81573271] ; National Natural Science Foundation of China[91229205] ; National Natural Science Foundation of China[81473243] ; National Natural Science Foundation of China[81321092] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09304002-008-001] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301001-007] ; Funding of Shanghai Institute of Materia Medica[CASIMM0120152005] ; Funding of Shanghai Institute of Materia Medica[CASIMM01d20151011] ; Chinese Academy of Sciences "Strategic Priority Research Program"[XDA12020303]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000380730600008
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/275947]  
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; Geng, Meiyu; Duan, Wenhu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
2.East China Univ Sci & Technol, Sch Pharm, 130 Mei Long Rd, Shanghai 200237, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;
5.Shanghai Univ, Coll Sci, Dept Chem, 99 Shang Da Rd, Shanghai 200111, Peoples R China;
6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Yan, Wei,Wang, Xinyi,Dai, Yang,et al. Discovery of 3-(5 '-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(14):6690-6708.
APA Yan, Wei.,Wang, Xinyi.,Dai, Yang.,Zhao, Bin.,Yang, Xinying.,...&Duan, Wenhu.(2016).Discovery of 3-(5 '-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation.JOURNAL OF MEDICINAL CHEMISTRY,59(14),6690-6708.
MLA Yan, Wei,et al."Discovery of 3-(5 '-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation".JOURNAL OF MEDICINAL CHEMISTRY 59.14(2016):6690-6708.

入库方式： OAI收割

来源：上海药物研究所

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