Chao Wang , Yazhou Wang , Fanye Meng , Tingting Liu , Xiaomin Wang , Xin Cai , Man Zhang , Alex Aliper , Feng Ren , Alex Zhavoronkov , Xiao Ding
{"title":"发现吡咯并嘧啶酮衍生物作为治疗癌症的强效 PKMYT1 抑制剂","authors":"Chao Wang , Yazhou Wang , Fanye Meng , Tingting Liu , Xiaomin Wang , Xin Cai , Man Zhang , Alex Aliper , Feng Ren , Alex Zhavoronkov , Xiao Ding","doi":"10.1016/j.ejmech.2024.117025","DOIUrl":null,"url":null,"abstract":"<div><div>The protein kinase PKMYT1 is responsible for inhibitory CDK1 phosphorylation, thus playing a central role in regulating the G2/M cell cycle checkpoint. As many cancers have dysfunctional cell cycle checkpoint signaling, PKMYT1 inhibition is emerging as an attractive target in advanced tumors. PKMYT1 inhibitors, however, have encountered difficulties in balancing biological efficacy, on-target specificity, and favorable stability and other drug-like properties. Herein, we report the design and development of pyrrolopyrimidinone derivatives intended to simultaneously restrict molecular conformation and shield a metabolic site in order to optimize stability. Compound <strong>7</strong> demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy <em>in vitro</em>, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor <em>in vivo</em> efficacy. Our findings indicate that compound <strong>7</strong> is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117025"},"PeriodicalIF":6.0000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of pyrrolopyrimidinone derivatives as potent PKMYT1 inhibitors for the treatment of cancer\",\"authors\":\"Chao Wang , Yazhou Wang , Fanye Meng , Tingting Liu , Xiaomin Wang , Xin Cai , Man Zhang , Alex Aliper , Feng Ren , Alex Zhavoronkov , Xiao Ding\",\"doi\":\"10.1016/j.ejmech.2024.117025\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>The protein kinase PKMYT1 is responsible for inhibitory CDK1 phosphorylation, thus playing a central role in regulating the G2/M cell cycle checkpoint. As many cancers have dysfunctional cell cycle checkpoint signaling, PKMYT1 inhibition is emerging as an attractive target in advanced tumors. PKMYT1 inhibitors, however, have encountered difficulties in balancing biological efficacy, on-target specificity, and favorable stability and other drug-like properties. Herein, we report the design and development of pyrrolopyrimidinone derivatives intended to simultaneously restrict molecular conformation and shield a metabolic site in order to optimize stability. Compound <strong>7</strong> demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy <em>in vitro</em>, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor <em>in vivo</em> efficacy. Our findings indicate that compound <strong>7</strong> is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.</div></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"281 \",\"pages\":\"Article 117025\"},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-11-05\",\"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/S0223523424009073\",\"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/S0223523424009073","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of pyrrolopyrimidinone derivatives as potent PKMYT1 inhibitors for the treatment of cancer
The protein kinase PKMYT1 is responsible for inhibitory CDK1 phosphorylation, thus playing a central role in regulating the G2/M cell cycle checkpoint. As many cancers have dysfunctional cell cycle checkpoint signaling, PKMYT1 inhibition is emerging as an attractive target in advanced tumors. PKMYT1 inhibitors, however, have encountered difficulties in balancing biological efficacy, on-target specificity, and favorable stability and other drug-like properties. Herein, we report the design and development of pyrrolopyrimidinone derivatives intended to simultaneously restrict molecular conformation and shield a metabolic site in order to optimize stability. Compound 7 demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy in vitro, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor in vivo efficacy. Our findings indicate that compound 7 is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.
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.