{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["11"],"submitter":["Fan M"],"funding":["Epiphanes","Hale Family Center for Pancreatic Cancer Research"],"pubmed_abstract":["The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic <i>BMF</i> gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration."],"journal":["eLife"],"pagination":["e78810"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9728995"],"repository":["biostudies-literature"],"pubmed_title":["Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling."],"pmcid":["PMC9728995"],"pubmed_authors":["Jiang J","Lu W","Tse J","Rees MG","Gokhale PC","Che J","Geffken EA","Mancias JD","Ronan MM","Liu Y","Song K","Dhe-Paganon S","Ficarro SB","Roth JA","Boghossian AS","Kuljanin M","Fan M","Seo HS","Marto JA","Zhang T","Gray NS","Lakhani J","Kwiatkowski NP","Ji W","He Z","Gao Y"],"additional_accession":[]},"is_claimable":false,"name":"Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling.","description":"The transcription factor TEAD, together with its coactivator YAP/TAZ, is a key transcriptional modulator of the Hippo pathway. Activation of TEAD transcription by YAP has been implicated in a number of malignancies, and this complex represents a promising target for drug discovery. However, both YAP and its extensive binding interfaces to TEAD have been difficult to address using small molecules, mainly due to a lack of druggable pockets. TEAD is post-translationally modified by palmitoylation that targets a conserved cysteine at a central pocket, which provides an opportunity to develop cysteine-directed covalent small molecules for TEAD inhibition. Here, we employed covalent fragment screening approach followed by structure-based design to develop an irreversible TEAD inhibitor MYF-03-69. Using a range of in vitro and cell-based assays we demonstrated that through a covalent binding with TEAD palmitate pocket, MYF-03-69 disrupts YAP-TEAD association, suppresses TEAD transcriptional activity and inhibits cell growth of Hippo signaling defective malignant pleural mesothelioma (MPM). Further, a cell viability screening with a panel of 903 cancer cell lines indicated a high correlation between TEAD-YAP dependency and the sensitivity to MYF-03-69. Transcription profiling identified the upregulation of proapoptotic <i>BMF</i> gene in cancer cells that are sensitive to TEAD inhibition. Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Oct","modification":"2026-05-29T14:58:20.449Z","creation":"2025-04-04T23:36:39.418Z"},"accession":"S-EPMC9728995","cross_references":{"pubmed":["36300789"],"doi":["10.7554/eLife.78810"]}}