Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations

doi:10.1016/j.bmcl.2018.03.087

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	Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations
	Zhu, Kongkai 2; Jiang, Chengshi 2; Tao, Hongrui 2; Liu, Jingqiu 1; Zhang, Hua 2; Luo, Cheng1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2018-05-15
卷号	28 期号:9 页码:1476-1483
关键词	PRMT5 inhibitor Resynthesis Virtual screening Molecular docking Molecular dynamics simulation
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2018.03.087
文献子类	Article
英文摘要	As one of the most promising anticancer target in protein arginine methyltransferase (PRMT) family, PRMT5 has been drawing more and more attentions, and many efforts have been devoted to develop its inhibitors. In this study, three PRMT5 inhibitors (9, 16, and 23) with novel scaffolds were identified by performing pharmacophore-and docking-based virtual screening combined with in vitro radiometric- based scintillation proximity assay (SPA). Substructure search based on the scaffold of the most active 9 afforded 26 additional analogues, and SPA results indicated that two analogues (9-1 and 9-2) showed increased PRMT5 inhibitory activity compared with the parental compound. Resynthesis of 9, 9-1, and 92 confirmed their PRMT5 enzymatic inhibition activity. In addition, compound 9-1 displayed selectivity against PRMT5 over other key homological members (PRMT1 and CARM1 (PRMT4)). While the structureactivity relationship (SAR) of this series of compounds was discussed to provide clues for further structure optimization, the probable binding modes of active compounds were also probed by molecular docking and molecular dynamics simulations. Finally, the antiproliferative effect of 9-1 on MV4-11 leukemia cell line was confirmed and its impact on regulating the target gene of PRMT5 was also validated. The hit compounds identified in this work have provided more novel scaffolds for future hit-to-lead optimization of small-molecule PRMT5 inhibitors. (C) 2018 Elsevier Ltd. All rights reserved.
资助项目	Natural Science Foundation of Shandong Province[ZR2017BH038] ; Natural Science Foundation of Shandong Province[JQ201721] ; Natural Science Foundation of China[21672082] ; Shandong Key Development Project[2016GSF201209] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027]
WOS关键词	GROWTH-CONTROL ; BREAST-CANCER ; METHYLATION ; EXPRESSION ; PHOSPHORYLATION ; OPTIMIZATION ; ACTIVATION ; CROSSTALK ; E2F-1
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000432493900008
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279758]
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
通讯作者	Zhang, Hua; Luo, Cheng
作者单位	1.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China;
推荐引用方式 GB/T 7714	Zhu, Kongkai,Jiang, Chengshi,Tao, Hongrui,et al. Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2018,28(9):1476-1483.
APA	Zhu, Kongkai,Jiang, Chengshi,Tao, Hongrui,Liu, Jingqiu,Zhang, Hua,&Luo, Cheng.(2018).Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,28(9),1476-1483.
MLA	Zhu, Kongkai,et al."Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 28.9(2018):1476-1483.