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Discovering potent inhibitors against c-Met kinase: molecular design, organic synthesis and bioassay

文献类型：期刊论文

作者Liang, Zhongjie1; Ding, Xiao1; Ai, Jing2; Kong, Xiangqian1; Chen, Limin1; Chen, Liang1; Luo, Cheng1,3; Geng, Meiyu2; Liu, Hong1; Chen, Kaixian1
刊名ORGANIC & BIOMOLECULAR CHEMISTRY
出版日期2012
卷号10期号:2页码:421-430
ISSN号1477-0520
DOI10.1039/c1ob06186k
文献子类Article
英文摘要The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. The discovery of small molecule inhibitors is of special interest in the blockade of the c-Met kinase pathway. Here, we initiated our study from compound 1a, a novel inhibitor against c-Met kinase. A substructure similarity search against the SPECS database and chemical synthesis methods were performed to obtain a series of pyrazolidine-3,5-dione derivatives. Through the enzyme-based assay against c-Met kinase, 4 compounds (1c, 1e, 1m and 1o) showed potential inhibitory activity, with IC50 values mostly less than 10 mu M. Based on the structure-activity relationship (SAR) and binding mode analysis, a focused combinatorial library was designed by the LD1.0 program. Taking into account ADMET properties and synthesis accessibility, seven candidate compounds (5a-g) were successfully synthesized. The activity of the most potent compounds 5b (IC50 = 0.46 mu M) was 20 fold higher than that of the lead 1a. Taken together, our findings identified the pyrazolidine-3,5-dione derivatives as potent inhibitors against c-Met kinase and demonstrated the efficiency of the strategy in the development of small molecules against c-Met kinase.
WOS关键词THERAPEUTIC TARGET ; SIGNALING PATHWAY ; CANCER ; ANGIOGENESIS ; AUTODOCK ; DOCKING ; HGF/MET ; NK4
资助项目National Natural Science Foundation of China[20972174] ; National Natural Science Foundation of China[81025017] ; National Natural Science Foundation of China[30725046] ; National Natural Science Foundation of China[91029704] ; National Natural Science Foundation of China[21021063] ; State Key Program of Basic Research of China[2009CB918502] ; Shanghai Committee of Science and Technology[10410703900] ; Chinese Academy of Sciences[XDA01040305] ; Guangdong ST Dept.[2010A030100006] ; Program of Shanghai Subject Chief Scientist[10XD1405100]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000298555700031
出版者ROYAL SOC CHEMISTRY
源URL[http://119.78.100.183/handle/2S10ELR8/278291]  
专题药物发现与设计中心
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
药理学第一研究室
通讯作者Luo, Cheng
作者单位1.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China;
3.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Jiangsu, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Zhongjie,Ding, Xiao,Ai, Jing,et al. Discovering potent inhibitors against c-Met kinase: molecular design, organic synthesis and bioassay[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2012,10(2):421-430.
APA Liang, Zhongjie.,Ding, Xiao.,Ai, Jing.,Kong, Xiangqian.,Chen, Limin.,...&Jiang, Hualiang.(2012).Discovering potent inhibitors against c-Met kinase: molecular design, organic synthesis and bioassay.ORGANIC & BIOMOLECULAR CHEMISTRY,10(2),421-430.
MLA Liang, Zhongjie,et al."Discovering potent inhibitors against c-Met kinase: molecular design, organic synthesis and bioassay".ORGANIC & BIOMOLECULAR CHEMISTRY 10.2(2012):421-430.

入库方式： OAI收割

来源：上海药物研究所

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