Direct targeting of β-catenin: Inhibition of protein-protein interactions for the inactivation of Wnt signaling

The activation of developmental signaling pathways such as Notch, Hedgehog and Wnt has implications in the onset and progression of numerous types of cancer. Consequently, targeting of such pathways is considered an attractive therapeutic approach. Inhibition of the Wnt signaling cascade proves to be complicated, in part, due to the lack of druggable pathway components. The central hub in Wnt signaling is the protein β-catenin, which is involved in numerous protein-protein interactions. In general, the inhibition of protein-protein interactions is challenging in particular with binding interfaces lacking pronounced hydrophobic pockets. Herein, we give an overview of β-catenin-protein interactions, and we review active agents that were reported to inhibit canonical Wnt signaling via direct targeting of β-catenin.