一石二鸟:将哌嗪引入一系列核苷衍生物作为强效和选择性 PRMT5 抑制剂

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-10-19 DOI:10.1016/j.ejmech.2024.116970
Huaxuan Li , Hong Yang , Li Liu , Jiahong Zheng , Qiongyu Shi , Bang Li , Xingcan Wang , Ying Zhang , Ruilin Zhou , Jian Zhang , Zhong-Zhu Chen , Chang-Yun Wang , Yuanxiang Wang , Xun Huang , Zhiqing Liu
{"title":"一石二鸟:将哌嗪引入一系列核苷衍生物作为强效和选择性 PRMT5 抑制剂","authors":"Huaxuan Li ,&nbsp;Hong Yang ,&nbsp;Li Liu ,&nbsp;Jiahong Zheng ,&nbsp;Qiongyu Shi ,&nbsp;Bang Li ,&nbsp;Xingcan Wang ,&nbsp;Ying Zhang ,&nbsp;Ruilin Zhou ,&nbsp;Jian Zhang ,&nbsp;Zhong-Zhu Chen ,&nbsp;Chang-Yun Wang ,&nbsp;Yuanxiang Wang ,&nbsp;Xun Huang ,&nbsp;Zhiqing Liu","doi":"10.1016/j.ejmech.2024.116970","DOIUrl":null,"url":null,"abstract":"<div><div>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 <strong>36</strong> exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound <strong>36</strong> 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 <strong>36</strong> had more favorable metabolic stability and aqueous solubility than JNJ64619178 (<strong>9</strong>). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that <strong>36</strong> is a highly potent and selective PRMT5 inhibitor worthy for further development.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 116970"},"PeriodicalIF":6.0000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors\",\"authors\":\"Huaxuan Li ,&nbsp;Hong Yang ,&nbsp;Li Liu ,&nbsp;Jiahong Zheng ,&nbsp;Qiongyu Shi ,&nbsp;Bang Li ,&nbsp;Xingcan Wang ,&nbsp;Ying Zhang ,&nbsp;Ruilin Zhou ,&nbsp;Jian Zhang ,&nbsp;Zhong-Zhu Chen ,&nbsp;Chang-Yun Wang ,&nbsp;Yuanxiang Wang ,&nbsp;Xun Huang ,&nbsp;Zhiqing Liu\",\"doi\":\"10.1016/j.ejmech.2024.116970\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <strong>36</strong> exhibited highly potent PRMT5 inhibition activity as well as good selectivity over other methyltransferases. Further cellular experiments revealed that compound <strong>36</strong> 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 <strong>36</strong> had more favorable metabolic stability and aqueous solubility than JNJ64619178 (<strong>9</strong>). Meanwhile, it obviously suppressed the tumor growth in a MOLM-13 tumor xenograft model. These results clearly indicate that <strong>36</strong> is a highly potent and selective PRMT5 inhibitor worthy for further development.</div></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"281 \",\"pages\":\"Article 116970\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-10-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0223523424008511\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523424008511","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0

摘要

蛋白精氨酸甲基转移酶 5(PRMT5)已成为治疗癌症的潜在靶点。人们一直在努力开发针对 S-腺苷蛋氨酸(SAM)口袋或底物结合口袋的强效、选择性 PRMT5 抑制剂。在这里,我们合理地设计了一系列与哌嗪结合的核苷衍生物,作为新型的 PRMT5 抑制剂,同时占据这两个口袋。具有代表性的化合物 36 表现出极强的 PRMT5 抑制活性,并且对其他甲基转移酶具有良好的选择性。进一步的细胞实验发现,化合物 36 能有效降低对称二甲基精氨酸(sDMA)的水平,并通过诱导细胞凋亡和细胞周期停滞来抑制 MOLM-13 细胞株的增殖。此外,化合物 36 比 JNJ64619178(9)具有更好的代谢稳定性和水溶性。同时,它在 MOLM-13 肿瘤异种移植模型中明显抑制了肿瘤的生长。这些结果清楚地表明,36 是一种高效且具有选择性的 PRMT5 抑制剂,值得进一步开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
One stone two birds: Introducing piperazine into a series of nucleoside derivatives as potent and selective PRMT5 inhibitors
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.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
期刊最新文献
Antibacterial and Antifungal Pyrazoles Based on Different Construction Strategies Discovery of Potent and Selective Factor XIa Inhibitors Incorporating Triazole-Based Benzoic Acid as Novel P2’ Fragments: Molecular Dynamics Simulations and Anticoagulant Activity Design, synthesis, and biological evaluation of novel highly potent FXR agonists bearing piperidine scaffold Design, synthesis and anti-tumor evaluation of novel pyrimidine and quinazoline analogues Optimization of SHP2 Allosteric Inhibitors with Novel Tail Heterocycles and Their Potential as Antitumor Therapeutics
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1