Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

The Wnt/beta-catenin signaling pathway plays a major role in tissue homeostasis, and its dysregulation can lead to various human diseases. Aberrant activation of beta-catenin is oncogenic and is a critical driver in the development and progression of human cancers. Despite the significant potential of targeting the oncogenic beta-catenin pathway for cancer therapy, the development of specific inhibitors remains insufficient. Using a T cell factor (TCF)-dependent luciferase-reporter system, we screened for small-molecule compounds that act against Wnt/beta-catenin signaling and identified MSAB (methyl 3-{[(4-methylphenyl) sulfonyl]amino}benzoate) as a selective inhibitor of Wnt/beta-catenin signaling. MSAB shows potent anti-tumor effects selectively on Wnt-dependent cancer cells in vitro and in mouse cancer models. MSAB binds to beta-catenin, promoting its degradation, and specifically downregulates Wnt/beta-catenin target genes. Our findings might represent an effective therapeutic strategy for cancers addicted to the Wnt/beta-catenin signaling pathway.