中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 药物化学研究室
Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization

文献类型：期刊论文

作者Mao, Ruifeng1,2; Shao, Jingwei4,5; Zhu, Kongkai2,6; Zhang, Yuanyuan2; Ding, Hong2; Zhang, Chenhua7; Shi, Zhe7; Jiang, Hualiang2; Sun, Dequn1; Duan, Wenhu4
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2017-07-27
卷号60期号:14页码:6289-6304
ISSN号0022-2623
DOI10.1021/acs.jmedchem.7b00587
文献子类Article
英文摘要PRMT5 plays important roles in diverse cellular processes and is upregulated in several hutnan malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 mu M) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding, of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a K-d of 0.987 mu M. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.
WOS关键词BIOLOGICAL EVALUATION ; ACCURATE DOCKING ; SM PROTEINS ; COMPLEX 2 ; IN-VIVO ; METHYLATION ; GROWTH ; DISCOVERY ; LYMPHOMA ; CANCER
资助项目Chinese Academy of Sciences[XDA12020304] ; Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21210003] ; National Natural Science Foundation of China[81230076] ; Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science[TMC201505] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027] ; China Postdoctoral Science Foundation[2016M601676] ; Shanghai Sailing Program[17YF1423100]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000406727700022
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/272556]  
专题药物化学研究室
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
药物发现与设计中心
通讯作者Sun, Dequn; Duan, Wenhu; Luo, Cheng
作者单位1.Shandong Univ, Marine Coll, Weihai 264209, Peoples R China;
2.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
4.Chinese Acad Sci, Dept Med Chem, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
6.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China;
7.Shanghai ChemPartner Co LTD, Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Mao, Ruifeng,Shao, Jingwei,Zhu, Kongkai,et al. Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization[J]. JOURNAL OF MEDICINAL CHEMISTRY,2017,60(14):6289-6304.
APA Mao, Ruifeng.,Shao, Jingwei.,Zhu, Kongkai.,Zhang, Yuanyuan.,Ding, Hong.,...&Luo, Cheng.(2017).Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization.JOURNAL OF MEDICINAL CHEMISTRY,60(14),6289-6304.
MLA Mao, Ruifeng,et al."Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization".JOURNAL OF MEDICINAL CHEMISTRY 60.14(2017):6289-6304.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。