Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity

doi:10.1007/s10822-019-00214-y

	Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity
	Zhu, Kongkai 3; Shao, Jingwei 1; Tao, Hongrui 3; Yan, Xue 3; Luo, Cheng 2; Zhang, Hua 3; Duan, Wenhu 1
刊名	JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
	2019-08-01
卷号	33 期号:8 页码:775-785
关键词	PRMT5 inhibitor Anti-proliferative Cellular target validation Design and synthesis
ISSN号	0920-654X
DOI	10.1007/s10822-019-00214-y
通讯作者	Zhu, Kongkai(hkhhh.k@163.com) ; Zhang, Hua(bio_zhangh@ujn.edu.cn) ; Duan, Wenhu(whduan@simm.ac.cn)
英文摘要	Protein arginine methyltransferase 5 (PRMT5) is responsible for the mono-methylation and symmetric dimethylation of arginine, and its expression level and methyl transferring activity have been demonstrated to have a close relationship with tumorigenesis, development and poor clinical outcomes of human cancers. Two PRMT5 small molecule inhibitors (GSK3326595 and JNJ-64619178) have been put forward into clinical trials. Here, we describe the design, synthesis and biological evaluation of a series of novel, potent and selective PRMT5 inhibitors with antiproliferative activity against Z-138 mantle cell lymphoma cell line. Among them, compound C_4 exhibited the highest potency with enzymatic and cellular level IC50 values of 0.72 and 2.6 mu M, respectively, and displayed more than 270-fold selectivity toward PRMT5 over several other isoenzymes (PRMT1, PRMT4 and PRMT6). Besides, C_4 demonstrated obvious cell apoptotic effect while reduced the cellular symmetric arginine dimethylation levels of SmD3 protein. The potency, small size, and synthetic accessibility of this compound class provide promising hit scaffold for medicinal chemists to further explore this series of PRMT5 inhibitors.
资助项目	National Natural Science Foundation of China[81803438] ; National Science and Technology Major Project[2018ZX09711002-004-013] ; Shandong Provincial Natural Science Foundation[JQ201721] ; Shandong Provincial Natural Science Foundation[ZR2017BH038] ; Young Taishan Scholars Program[tsqn20161037] ; Shandong Talents Team Cultivation Plan of University Preponderant Discipline[10027]
WOS关键词	ARGININE METHYLTRANSFERASE 5 ; CELL-DEATH ; PROTEIN ; METHYLATION ; IDENTIFICATION ; GROWTH ; PATHWAY
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics ; Computer Science
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000488949200006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/282576]
专题	中国科学院上海药物研究所
通讯作者	Zhu, Kongkai; Zhang, Hua; Duan, Wenhu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res,Drug Discovery & Design Ct, Shanghai 201203, Peoples R China 3.Univ Jinan, Sch Biol Sci & Technol, Jinan 250022, Shandong, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Kongkai,Shao, Jingwei,Tao, Hongrui,et al. Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity[J]. JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,2019,33(8):775-785.
APA	Zhu, Kongkai.,Shao, Jingwei.,Tao, Hongrui.,Yan, Xue.,Luo, Cheng.,...&Duan, Wenhu.(2019).Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity.JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN,33(8),775-785.
MLA	Zhu, Kongkai,et al."Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity".JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 33.8(2019):775-785.