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

Abstract 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.