One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors
文献类型：期刊论文
| 作者 | Li, Huaxuan3,4,5,9; Yang, Hong6; Liu, Li5; Zheng, Jiahong5; Shi, Qiongyu6; Li, Bang5; Wang, Xingcan7; Zhang, Ying6,8; Zhou, Ruilin10; Zhang, Jian1 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-01-05 |
| 卷号 | 281页码:18 |
| 关键词 | Protein arginine methyltransferase 5 Nucleoside derivatives Piperazine Metabolic stability Symmetric dimethylarginines |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2024.116970 |
| 通讯作者 | Wang, Chang-Yun(changyun@ouc.edu.cn) ; Wang, Yuanxiang(wangyx95@mail.sysu.edu.cn) ; Huang, Xun(xhuang@simm.ac.cn) ; Liu, Zhiqing(liuzhiqing@ouc.edu.cn) |
| 英文摘要 | The protein arginine methyltransferase 5 (PRMT5) has emerged as potential target for the treatment of cancer. Many efforts have been made to develop potent and selective PRMT5 inhibitors targeting either S-adenosyl methionine (SAM) pocket or substrate binding pocket. Here, we rationally designed a series of nucleoside derivatives incorporated with piperazine as novel PRMT5 inhibitors occupying both pockets. The representative compound 36 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound 36 potently reduced the level of symmetric dimethylarginines (sDMA) and inhibited the proliferation of MOLM-13 cell lines by inducing apoptosis and cell cycle arrest. Moreover, compound 36 had more favorable metabolic stability and aqueous solubility than JNJ64619178 (9). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that 36 is a highly potent and selective PRMT5 inhibitor worthy for further development. |
| WOS关键词 | ARGININE METHYLTRANSFERASE 5 ; METHYLATION ; JNJ-64619178 ; DISCOVERY ; DELETION |
| 资助项目 | National Natural Science Foundation of China[42176109] ; National Natural Science Foundation of China[82173835] ; Funda-mental Research Funds for the Central Universities[202241008] ; Taishan Scholars Program of Shandong Province ; Program of Shanghai Subject Chief Scientist[22XD1425300] ; Guangdong Basic and Applied Basic Research Foundation[2022A1515010951] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001350392700001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/314376]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Chang-Yun; Wang, Yuanxiang; Huang, Xun; Liu, Zhiqing |
| 作者单位 | 1.Sun Yat Sen Univ, Affiliated Hosp 3, Affiliated Hosp 3, Guangzhou 510630, Peoples R China 2.Shanghai Jiao Tong Univ, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China 3.Ocean Univ China, Inst Evolut & Marine Biodivers, Sch Med & Pharm, Key Lab Evolut & Marine Biodivers, Qingdao 266003, Peoples R China 4.Qingdao Marine Sci & Technol Ctr, Lab Marine Drugs & Bioprod, Qingdao 266237, Peoples R China 5.Sun Yat Sen Univ, Sch Pharmaceut Sci, Balance Based Drug Discovery Lab, Guangzhou 510006, Peoples R China 6.Lingang Lab, Shanghai 200031, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 8.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 9.Ocean Univ China, MOE Key Lab Marine Drugs, Qingdao 266003, Peoples R China 10.Nanjing Univ Chinese Med, Sch Holist Integrat Med, Nanjing 210023, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Huaxuan,Yang, Hong,Liu, Li,et al. One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,281:18. |
| APA | Li, Huaxuan.,Yang, Hong.,Liu, Li.,Zheng, Jiahong.,Shi, Qiongyu.,...&Liu, Zhiqing.(2025).One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,281,18. |
| MLA | Li, Huaxuan,et al."One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 281(2025):18. |
入库方式： OAI收割
来源：上海药物研究所
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