Targeting β-catenin: PROTACs and precision degraders for Wnt-driven cancers

TL;DR

This review discusses the challenges and strategies for targeting β-catenin in Wnt-driven cancers, focusing on new drug approaches like PROTACs.

Contribution

The paper provides insights into overcoming on-target toxicity while targeting β-catenin for cancer therapy.

Findings

Current Wnt inhibitors target upstream components rather than β-catenin, the most mutated downstream protein.

Developing drugs like PROTACs and precision degraders shows promise for targeting β-catenin in Wnt-driven cancers.

On-target toxicity from cadherin-bound β-catenin remains a key challenge in drug development.

Abstract

The Wnt signaling pathway, a highly conserved molecular cascade, orchestrates critical biological processes including embryonic development, cell differentiation, and proliferation across diverse organisms. Despite the pivotal role that Wnt signaling plays in many diseases, most notably cancer, there are still no FDA-approved, efficacious drugs available that inhibit this pathway. Most Wnt inhibitors target upstream components (e.g., Wnt ligand production and receptors) rather than the most commonly mutated downstream proteins in the pathway. Consequently, there is considerable interest in developing drugs that target the downstream effector, β-catenin. This review examines the challenges in targeting β-catenin, current approaches, and insights into overcoming on-target toxicity associated with cadherin-bound β-catenin.

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