Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization

doi:10.1021/acs.jmedchem.7b00587

	Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization
	Mao, Ruifeng 1,2; Shao, Jingwei 4,5; Zhu, Kongkai 2,6; Zhang, Yuanyuan 2; Ding, Hong2 ; Zhang, Chenhua 7; Shi, Zhe 7; Jiang, Hualiang2 ; Sun, Dequn 1; Duan, Wenhu4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2017-07-27
卷号	60 期号:14 页码:6289-6304
ISSN号	0022-2623
DOI	10.1021/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.
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关键词	BIOLOGICAL EVALUATION ; ACCURATE DOCKING ; SM PROTEINS ; COMPLEX 2 ; IN-VIVO ; METHYLATION ; GROWTH ; DISCOVERY ; LYMPHOMA ; CANCER
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000406727700022
内容类型	期刊论文
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.