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Over the past five years, the development of YAP\u2013TEAD disruptors has emerged as a central focus of both academic and industrial efforts aimed at targeting the Hippo pathway for cancer therapy. In this study, the discovery and comprehensive characterization of KG\u2010FP\u2010003, a potent, selective, and durable TEAD degrader is reported. KG\u2010FP\u2010003 exhibits superior activity compared to the lipid\u2010binding pocket (LBP) inhibitor MYF\u201003\u2010176 and the TEAD\u2013YAP protein\u2013protein interaction (PPI) inhibitor IAG933, efficiently degrading all TEAD isoforms at low nanomolar concentrations in a ubiquitin\u2013proteasome system (UPS)\u2010dependent manner. This degradation translates into more robust and sustained therapeutic responses both in vitro and in vivo. Furthermore, barcoded cell line screening revealed elevated sensitivity in several cancer types, including endometrial carcinoma, glioblastoma, ovarian epithelial tumors, and osteosarcoma. These findings position KG\u2010FP\u2010003 as a compelling lead candidate for TEAD isoform\u2010selective therapies and underscore its potential utility beyond Hippo\u2010dysregulated mesothelioma.<\/jats:p>","DOI":"10.1002\/advs.202503277","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T03:36:40Z","timestamp":1759721800000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity"],"prefix":"10.1002","volume":"12","author":[{"given":"Linhui","family":"Cao","sequence":"first","affiliation":[{"name":"School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of Education, China Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong Yantai University  Yantai 264005 China"},{"name":"Lingang Laboratory 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