Shiyang Zhai, , , Nicola Willemsen, , , Tao Sun, , , Mateo Malenica, , , Shixin Deng, , , Matthias Geyer, , and , Finn K. Hansen*,
{"title":"通过直接募集CUL4复合体接头蛋白DDB1的化学诱导接近靶向组蛋白去乙酰化酶降解","authors":"Shiyang Zhai, , , Nicola Willemsen, , , Tao Sun, , , Mateo Malenica, , , Shixin Deng, , , Matthias Geyer, , and , Finn K. Hansen*, ","doi":"10.1021/acsmedchemlett.5c00506","DOIUrl":null,"url":null,"abstract":"<p >Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for disease treatment. By recruiting E3 ligases, these molecules enable selective degradation of pathogenic proteins. Cereblon (CRBN), a key component of the CUL4-DDB1-CRBN E3 ligase complex, is the most commonly recruited E3 ligase in PROTACs, including those targeting histone deacetylases (HDACs). In this study, we designed <b>SZ-2</b>, a bifunctional molecule derived from the DDB1 ligand MM-02-57 and the HDAC inhibitor vorinostat, to simultaneously bind DDB1 and HDACs. <b>SZ-2</b> effectively induced degradation of HDAC1 and HDAC2 and demonstrated potent anti-multiple myeloma activity, highlighting its potential as a novel therapeutic agent.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 10","pages":"2070–2077"},"PeriodicalIF":4.0000,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted Histone Deacetylase Degradation via Chemical Induced Proximity by Direct Recruitment of the CUL4 Complex Adaptor Protein DDB1\",\"authors\":\"Shiyang Zhai, , , Nicola Willemsen, , , Tao Sun, , , Mateo Malenica, , , Shixin Deng, , , Matthias Geyer, , and , Finn K. Hansen*, \",\"doi\":\"10.1021/acsmedchemlett.5c00506\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for disease treatment. By recruiting E3 ligases, these molecules enable selective degradation of pathogenic proteins. Cereblon (CRBN), a key component of the CUL4-DDB1-CRBN E3 ligase complex, is the most commonly recruited E3 ligase in PROTACs, including those targeting histone deacetylases (HDACs). In this study, we designed <b>SZ-2</b>, a bifunctional molecule derived from the DDB1 ligand MM-02-57 and the HDAC inhibitor vorinostat, to simultaneously bind DDB1 and HDACs. <b>SZ-2</b> effectively induced degradation of HDAC1 and HDAC2 and demonstrated potent anti-multiple myeloma activity, highlighting its potential as a novel therapeutic agent.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":\"16 10\",\"pages\":\"2070–2077\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2025-09-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00506\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.5c00506","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Targeted Histone Deacetylase Degradation via Chemical Induced Proximity by Direct Recruitment of the CUL4 Complex Adaptor Protein DDB1
Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as a powerful strategy for disease treatment. By recruiting E3 ligases, these molecules enable selective degradation of pathogenic proteins. Cereblon (CRBN), a key component of the CUL4-DDB1-CRBN E3 ligase complex, is the most commonly recruited E3 ligase in PROTACs, including those targeting histone deacetylases (HDACs). In this study, we designed SZ-2, a bifunctional molecule derived from the DDB1 ligand MM-02-57 and the HDAC inhibitor vorinostat, to simultaneously bind DDB1 and HDACs. SZ-2 effectively induced degradation of HDAC1 and HDAC2 and demonstrated potent anti-multiple myeloma activity, highlighting its potential as a novel therapeutic agent.
期刊介绍：
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
