Discovery of a Potent and Selective TEAD Degrader with Durable Degradation Activity.

ABSTRACT: The TEA/ATSS (TEAD) family of transcription factors are key effectors of the Hippo pathway, exerting their function through interactions with the coactivators YAP and TAZ. Over the past five years, the development of YAP-TEAD 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-FP-003, a potent, selective, and durable TEAD degrader is reported. KG-FP-003 exhibits superior activity compared to the lipid-binding pocket (LBP) inhibitor MYF-03-176 and the TEAD-YAP protein-protein interaction (PPI) inhibitor IAG933, efficiently degrading all TEAD isoforms at low nanomolar concentrations in a ubiquitin-proteasome system (UPS)-dependent manner

SUBMITTER: Cao L 

PROVIDER: S-EPMC12752627 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature