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Here, we uncover an alternative mechanism for a subset of TEAD lipid pocket-binding molecules. We report that select sulfonamide-containing TEAD-targeting compounds enhance the interaction between TEAD and the transcriptional repressor VGLL4. Chemically induced VGLL4\u2013TEAD complexes confer an antiproliferative effect by outcompeting YAP\u2013TEAD complexes at chromatin. This cofactor switch from YAP to VGLL4 impacts transcriptional networks, including influencing the expression of genes involved in cellular proliferation and mechanosignaling. We demonstrate that VGLL4 is required for an antiproliferative response to these sulfonamide-containing compounds by counteracting YAP. We show that VGLL4 overexpression can confer sensitivity to these compounds in Hippo-driven cell lines, and we further show that genetic deletion of VGLL4 oblates cellular responsiveness to these molecules in cells and in vivo. Our data reveal a category of TEAD inhibitors that act as \u201cmolecular glues\u201d toward the repressive VGLL4\u2013TEAD interaction. These findings open up understandings for curbing the oncogenic activity of Hippo pathway deregulation in cancer, and identify glue-like molecules that promote transcriptional repression.<\/jats:p>","DOI":"10.1073\/pnas.2425984122","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T13:20:24Z","timestamp":1751548824000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["TEAD-targeting small molecules induce a cofactor switch to regulate the Hippo pathway"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4195-2158","authenticated-orcid":false,"given":"Alissa D.","family":"Guarnaccia","sequence":"first","affiliation":[{"name":"Department of Proteomic and Genomic Technologies, Genentech","place":["South San Francisco"]},{"name":"Department of Discovery Oncology, Genentech","place":["South San 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