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

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

Automated summary

Aberrant activation of the Wnt/beta-catenin signaling pathway is associated with cancer, and direct targeting of beta-catenin is a promising strategy but challenging. Research has identified potential small-molecule binding sites and summarized bioactive small molecules that target beta-catenin directly.