Rational Design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity
文献类型：期刊论文
| 作者 | Zhu, Kongkai3; Shao, Jingwei1; Tao, Hongrui3; Yan, Xue3; Luo, Cheng2 ; Zhang, Hua3; Duan, Wenhu1
|
| 刊名 | JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
 |
| 出版日期 | 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. |
| WOS关键词 | ARGININE METHYLTRANSFERASE 5 ; CELL-DEATH ; PROTEIN ; METHYLATION ; IDENTIFICATION ; GROWTH ; PATHWAY |
| 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研究方向 | Biochemistry & Molecular Biology ; Biophysics ; Computer Science |
| 语种 | 英语 |
| WOS记录号 | WOS:000488949200006 |
| 出版者 | SPRINGER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/282576]  |
| 专题 | 新药研究国家重点实验室 |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。