Direct targeting of β‐catenin in the Wnt signaling pathway: Current progress and perspectives

Aberrant activation of the Wnt/β-catenin signaling circuit is associated with cancer recurrence and relapse, cancer invasion and metastasis, and cancer immune evasion. Direct targeting of β-catenin, the central hub in this signaling pathway, is a promising strategy to suppress the hyperactive β-catenin signaling but has proven to be highly challenging. Substantial efforts have been made to discover compounds that bind with β-catenin, block β-catenin-mediated protein-protein interactions, and suppress β-catenin signaling. Herein, we characterize potential small-molecule binding sites in β-catenin, summarize bioactive small molecules that directly target β-catenin, and review structure-based inhibitor optimization, structure-activity relationship, and biological activities of reported inhibitors. This knowledge will benefit future inhibitor development and β-catenin-related drug discovery.