Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5
文献类型：期刊论文
| 作者 | Rong, Deqin5; Zhou, Kaixin2,3,4; Fang, Wei5; Yang, Hong3; Zhang, Yi5; Shi, Qiongyu3; Huang, Yuting2,3; Li, Jiayi2,3; Dong, Hui5; Li, Lanlan3 |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2022-06-09 |
| 卷号 | 65期号:11页码:7854-7875 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.2c00398 |
| 通讯作者 | Ding, Jian(jding@simm.ac.cn) ; Huang, Xun(xhuang@simm.ac.cn) ; Wang, Yuanxiang(wangyx95@mail.sysu.edu.cn) |
| 英文摘要 | PRMT5 is a major type II protein arginine methyltransferase and plays important roles in diverse cellular processes. Overexpression of PRMT5 is implicated in various types of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors, the most potent of which is usually derived from nucleoside structures. Here, we designed a novel series of non-nucleoside PRMT5 inhibitors through the structure-aided drug design approach. SAR exploration and metabolic stability optimization led to the discovery of compound 41 as a potent PRMT5 inhibitor with good selectivity. Additionally, compound 41 exerted antiproliferative effects against A375 cells by inducing apoptosis and potently inhibited the methyltransferase activity of PRMT5 in cells. Moreover, it showed attractive pharmacokinetic properties and markedly suppressed the tumor growth in an A375 tumor xenograft model. These results clearly indicate that 41 is a highly potent and selective non-nucleoside PRMT5 inhibitor. |
| WOS关键词 | PRMT5 ; METHYLATION ; DISCOVERY |
| 资助项目 | National Natural Science Foundation of China[21977128] ; National Natural Science Foundation of China[21922707] ; National Natural Science Foundation of China[82173835] ; Guangzhou Basic and Applied Basic Research Foundation[202103000097] ; Major projects of National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Munic-ipal Commission of Health and Family Planning[2019CXJQ02] ; Open Program of the State Key Laboratory of New Drug development[SIMM2105KF-04] ; SA-SIBS Scholarship Program ; Shanghai Municipal Science and Technology Major Project |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000810686800001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/301530]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Ding, Jian; Huang, Xun; Wang, Yuanxiang |
| 作者单位 | 1.Lingang Lab, Shanghai 200031, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Sun Yat Sen Univ, Sch Pharmaceut Sci, Balance Based Drug Discovery Lab, Guangzhou 510006, Peoples R China 6.Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Rong, Deqin,Zhou, Kaixin,Fang, Wei,et al. Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5[J]. JOURNAL OF MEDICINAL CHEMISTRY,2022,65(11):7854-7875. |
| APA | Rong, Deqin.,Zhou, Kaixin.,Fang, Wei.,Yang, Hong.,Zhang, Yi.,...&Wang, Yuanxiang.(2022).Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5.JOURNAL OF MEDICINAL CHEMISTRY,65(11),7854-7875. |
| MLA | Rong, Deqin,et al."Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5".JOURNAL OF MEDICINAL CHEMISTRY 65.11(2022):7854-7875. |
入库方式： OAI收割
来源：上海药物研究所
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