Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

doi:10.1111/cbdd.13047

	Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors
	Zhang, Wei-yao 2; Lu, Wen-chao 3,4; Jiang, Hao 3,4; Lv, Zheng-bing 2; Xie, Yi-qian 3; Lian, Fu-lin 3; Liang, Zhong-jie 5; Jiang, Yu-xi 1; Wang, Da-jin 2; Luo, Cheng3
刊名	CHEMICAL BIOLOGY & DRUG DESIGN
	2017-12
卷号	90 期号:6 页码:1260-1270
关键词	epigenetics molecular docking PRMT1 scaffold hopping small-molecule inhibitor
ISSN号	1747-0277
DOI	10.1111/cbdd.13047
文献子类	Article
英文摘要	Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1 inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors. Among them, the most potent compound corresponds to hexamidine (IC50=5.9 +/- 1.7m), which is an antimicrobial agent. The binding between hexamidine and PRMT1 was further validated by thermal shift assays and nuclear magnetic resonance (NMR) experiments. Molecular docking and NMR assays indicated that hexamidine occupied the substrate binding pocket. Furthermore, hexamidine effectively blocked cell proliferation in cancer cell lines related to PRMT1 overexpression. Taken together, this study has provided a druggable scaffold targeting PRMT1 as well as a new way to repurpose old drugs which is a complementary tool for the discovery of new lead compounds.
资助项目	Natural Science Foundation of China[81402849] ; Public Projects of Zhejiang Province[2015C33159] ; Public Projects of Zhejiang Province[2016C31017] ; Public Projects of Zhejiang Province[2015C37031] ; Zhejiang Provincial Top Key Discipline of Biology[00000000] ; Science Foundation of Zhejiang Sci-Tech University[13042163-Y] ; Science Foundation of Zhejiang Sci-Tech University[13042159-Y] ; China Postdoctoral Science Foundation[2013M531406] ; 521 Talent Cultivation Plan of Zhejiang SciTech University[00000000]
WOS关键词	SMALL-MOLECULE INHIBITORS ; BIOLOGICAL EVALUATION ; CELL-PROLIFERATION ; METHYLATION ; CANCER ; PHOSPHORYLATION ; IDENTIFICATION ; INTERACTS ; ANALOGS ; BINDING
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy
语种	英语
出版者	WILEY
WOS记录号	WOS:000415354300021
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272388]
专题	分析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	Jin, Jia; Ye, Fei
作者单位	1.Shanghai Jiao Tong Univ, Sch Pharm, Shanghai, Peoples R China; 2.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou, Zhejiang, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai, Peoples R China; 4.Univ Chinese Acad Sci, Beijing, Peoples R China; 5.Soochow Univ, Ctr Syst Biol, Suzhou, Jiangsu, Peoples R China; 6.Key Lab Plant Secondary Metab & Regulat Zhejiang, Hangzhou, Zhejiang, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Wei-yao,Lu, Wen-chao,Jiang, Hao,et al. Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors[J]. CHEMICAL BIOLOGY & DRUG DESIGN,2017,90(6):1260-1270.
APA	Zhang, Wei-yao.,Lu, Wen-chao.,Jiang, Hao.,Lv, Zheng-bing.,Xie, Yi-qian.,...&Ye, Fei.(2017).Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors.CHEMICAL BIOLOGY & DRUG DESIGN,90(6),1260-1270.
MLA	Zhang, Wei-yao,et al."Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors".CHEMICAL BIOLOGY & DRUG DESIGN 90.6(2017):1260-1270.