Is β-Catenin a Druggable Target for Cancer Therapy?

Mutations of canonical Wnt signaling pathway genes frequently occur in cancer and lead to abnormal accumulation of the key effector beta-catenin. Over the past decades, a number of Wnt inhibitors have been identified through high-throughput screenings, however, very few of them target beta-catenin directly, raising questions regarding its druggability. Here, we review Wnt inhibitors with a focus on small molecules that directly bind beta-catenin, discuss the druggability of beta-catenin, and why it has rarely been targeted, especially in the cellular context. We also propose strategies to develop small molecule binding and depleting cellular beta-catenin, which are generally applicable to other difficult-to-drug or yet-to-be-drugged targets.