Discovery of alkyl bis(oxy)dibenzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors
文献类型：期刊论文
| 作者 | Zhang, Wei-yao2; Lu, Wen-chao3,4; Jiang, Hao3,4; Lv, Zheng-bing2; Xie, Yi-qian3; Lian, Fu-lin3; Liang, Zhong-jie5; Jiang, Yu-xi1; Wang, Da-jin2; Luo, Cheng3
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| 刊名 | CHEMICAL BIOLOGY & DRUG DESIGN
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| 出版日期 | 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. |
| WOS关键词 | SMALL-MOLECULE INHIBITORS ; BIOLOGICAL EVALUATION ; CELL-PROLIFERATION ; METHYLATION ; CANCER ; PHOSPHORYLATION ; IDENTIFICATION ; INTERACTS ; ANALOGS ; BINDING |
| 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研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000415354300021 |
| 出版者 | WILEY |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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