9. Small-Molecule Inhibitors for the β-Catenin/T Cell Factor Protein-Protein Interaction

The aberrant activation of canonical Wnt signaling is strongly associated with the initiation and progression of many cancers. Cancer stem cells, which are resistant to conventional chemo- and radiotherapies and especially virulent, are also controlled by the hyperactivation of canonical Wnt signaling. Therefore, the disruption of this signaling pathway represents an attractive strategy for cancer therapy. The formation of the β-catenin/Tcf complex in the cell nucleus is the penultimate step of canonical Wnt signaling; hence, these protein-protein interactions (PPIs) were identified as an appealing therapeutic target for anticancer drug development. Herein, the approaches for the discovery of small-molecule inhibitors to disrupt the β-catenin/T cell factor protein-protein interaction, including high throughput screening (HTS), virtual screening, and hot spots-based rational design, were reviewed and the representative examples were presented. These novel inhibitors provide a good starting point for further research. Furthermore, the challenge and opportunity in this researching area, such as further improvement of the binding potency and selectivity, as well as the development of drug-like inhibitors for cell-based and in vivo studies were also discussed.