Covalent 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 CTNNB1. Our results show that chemoproteomic
approaches can be used to covalently target and degrade challenging
transcription factors like CTNNB1 through destabilization-mediated
degradation.