{"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":"","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":null,"pages":null},"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\":\"\",\"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\":null,\"pages\":null},\"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}
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.
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.