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Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors

文献类型：期刊论文

作者Chen, Yuting4,6; Wang, Zekun4,5,6; Zhang, Junjie4,6; Shi, Qiongyu3; Yang, Hong3; Deng, Yue4; Wang, Xingcan4; Liu, Tongchao1,6; Geng, Meiyu4; Xiong, Bing1,4,6
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-03-05
卷号267页码:19
关键词PRMT5 Nucleoside derivatives Methyltransferases Structure -activity relationship
ISSN号0223-5234
DOI10.1016/j.ejmech.2024.116171
通讯作者Liu, Tongchao(tongchao_liu@simm.ac.cn) ; Xiong, Bing(bxiong@simm.ac.cn) ; Huang, Xun(xhuang@lglab.ac.cn)
英文摘要The ubiquitous methyltransferases employing SAM as the methyl donor have emerged as potential targets in many disease treatments, especially in anticancer. Therefore, developing SAM-competitive inhibitors of methyltransferases is of great interest to the drug research. To explore this direction, herein, we rationally designed a series of nucleoside derivatives as potent PRMT5 inhibitors with novel scaffold. The representative compounds A2 and A8 exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other PRMTs and PKMTs. Further cellular experiments revealed that compounds A2 and A8 potently reduced the level of sDMA and inhibited the proliferation of Z-138 and MOLM-13 cell lines by inducing apoptosis. Moreover, compounds A8 which had favorable pharmacokinetic properties exhibited potent antitumor efficacy without the loss of body weight in a subcutaneous MOLM-13 xenograft model. In summary, our efforts provided a series of novel nucleoside analogs as potent PRMT5 inhibitors and may also offer a new strategy to develop SAM analogs as other methyltransferases' inhibitors.
WOS关键词METHYLTRANSFERASE 5 PRMT5 ; ARGININE METHYLTRANSFERASE
资助项目National Natural Science Foundation of China[82173658] ; National Natural Science Foundation of China[81773572] ; National Natural Science Foundation of China[82173835] ; National Natural Science Foundation of China[82204187] ; Shanghai Municipal Science and Technology Major Project[TM202101H010] ; Major projects of National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Program of Shanghai Subject Chief Scientist[22XD1425300] ; SA-SIBS Scholarship Program
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001174098300001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/310193]  
专题新药研究国家重点实验室
通讯作者Liu, Tongchao; Xiong, Bing; Huang, Xun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
2.UCAS, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
3.Lingang Lab, Shanghai 200031, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Yuting,Wang, Zekun,Zhang, Junjie,et al. Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,267:19.
APA Chen, Yuting.,Wang, Zekun.,Zhang, Junjie.,Shi, Qiongyu.,Yang, Hong.,...&Huang, Xun.(2024).Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,267,19.
MLA Chen, Yuting,et al."Structure-based discovery of a new series of nucleoside-derived ring-opening PRMT5 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 267(2024):19.

入库方式： OAI收割

来源：上海药物研究所

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