{"title":"转录增强同位结构域 (TEAD) PROTAC 降解剂的设计、合成和生物评估","authors":"Huajie Li, Zhiming Ge, Kexin Lin, Wei He, Qinyu Chu, Mingyue Zheng*, Sulin Zhang* and Tianfeng Xu*, ","doi":"10.1021/acsmedchemlett.4c00029","DOIUrl":null,"url":null,"abstract":"<p >Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, <b>27</b>, exhibited potent antiproliferative activity against <i>NF2</i>-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes <i>CYR61</i> and <i>CTGF</i> expressions in NCI-H226 cells. Further degradation selectivity studies revealed that <b>27</b> exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, <b>27</b> may serve as a valuable tool for advancing biological studies related to TEAD2.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders\",\"authors\":\"Huajie Li, Zhiming Ge, Kexin Lin, Wei He, Qinyu Chu, Mingyue Zheng*, Sulin Zhang* and Tianfeng Xu*, \",\"doi\":\"10.1021/acsmedchemlett.4c00029\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, <b>27</b>, exhibited potent antiproliferative activity against <i>NF2</i>-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes <i>CYR61</i> and <i>CTGF</i> expressions in NCI-H226 cells. Further degradation selectivity studies revealed that <b>27</b> exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, <b>27</b> may serve as a valuable tool for advancing biological studies related to TEAD2.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-04-22\",\"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.4c00029\",\"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.4c00029","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Design, Synthesis, and Bioevaluation of Transcriptional Enhanced Assocciated Domain (TEAD) PROTAC Degraders
Dysregulation of the Hippo pathway has been observed in various cancers. The transcription factor TEAD, together with its coactivators YAP/TAZ, plays a crucial role in regulating the transcriptional output of the Hippo pathway. Recently, extensive research has focused on small molecule inhibitors targeting TEAD, but studies on TEAD degraders are comparatively rare. In this study, we designed and synthesized a series of TEAD PROTACs by connecting a pan-TEAD inhibitor with the CRBN ligand thalidomide. A representative compound, 27, exhibited potent antiproliferative activity against NF2-deficient NCI-H226 cells. It dose-dependently induced TEAD degradation dependent on CRBN and proteasome system and decreased key YAP target genes CYR61 and CTGF expressions in NCI-H226 cells. Further degradation selectivity studies revealed that 27 exhibited more potent activity against TEAD2 compared to those of the other three family members in Flag-TEADs transfected 293T cells. Therefore, 27 may serve as a valuable tool for advancing biological studies related to TEAD2.
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.