biostudies-literatureUnknownGowans FABristol-Myers SquibbMark Foundation For Cancer ResearchNational Cancer InstituteNCI NIH HHSNIH HHSNomura Research Groupβ-catenin (CTNNB1) is an oncogenic transcription factor that is important in cell-cell adhesion and transcription of cell proliferation and survival genes that drive the pathogenesis of many different types of cancers. However, direct pharmacological targeting of CTNNB1 has remained challenging. Here, we have performed a screen with a library of cysteine-reactive covalent ligands to identify the monovalent degrader EN83 that depletes CTNNB1 in a ubiquitin-proteasome-dependent manner. We show that EN83 directly and covalently targets CTNNB1 three cysteines C466, C520, and C619, leading to destabilization and degradation of CTNNB1. Through structural optimization, we generate a highly potent and relatively selective destabilizing degrader that acts through the targeting of only C619 on CTNNBJournal of the American Chemical Societyhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC12102902biostudies-literatureCovalent Degrader of the Oncogenic Transcription Factor β-Catenin.PMC12102902S10 OD024998R01 CA240981R35 CA263814R35CA263814R01CA240981Forte NNomura DKAltamirano Poblano BEHuang OWHatcher JWang YWertz IEGowans FAfalseCovalent Degrader of the Oncogenic Transcription Factor β-Catenin.β-catenin (CTNNB1) is an oncogenic transcription factor that is important in cell-cell adhesion and transcription of cell proliferation and survival genes that drive the pathogenesis of many different types of cancers. However, direct pharmacological targeting of CTNNB1 has remained challenging. Here, we have performed a screen with a library of cysteine-reactive covalent ligands to identify the monovalent degrader EN83 that depletes CTNNB1 in a ubiquitin-proteasome-dependent manner. We show that EN83 directly and covalently targets CTNNB1 three cysteines C466, C520, and C619, leading to destabilization and degradation of CTNNB1. Through structural optimization, we generate a highly potent and relatively selective destabilizing degrader that acts through the targeting of only C619 on CTNNB2024-01-01T00:00:00Z2024 Jun2026-06-05T22:29:36.486Z2026-05-22T03:16:13.752ZS-EPMC121029023884825210.1021/jacs.4c05174