Structure-Based Discovery of a Novel Inhibitor Targeting the β-Catenin/Tcf4 Interaction

Overactivation or overexpression of beta-catenin in the Wnt (wingless) signaling pathway plays an important role in tumorigenesis. Interaction of beta-catenin with T-cell factor (Tcf) DNA binding proteins is a key step in the activation of the proliferative genes in response to upstream signals of this Wnt/beta-catenin pathway. Recently, we identified a new small molecule inhibitor, named BC21 (C32H36Cl2Cu2N2O2), which effectively inhibits the binding of beta-catenin with Tcf4-derived peptide and suppresses beta-catenin/Tcf4 driven reporter gene activity. This inhibitor decreases the viability of beta-catenin overexpressing HCT116 colon cancer cells that harbor the beta-catenin mutation, and more significantly, it inhibits the clonogenic activity of these cells. Down-regulation of c-Myc and cyclin D1 expression, the two important effectors of the Wnt/beta-catenin signaling, is confirmed by treating HCT116 cells with BC21. This compound represents a new and modifiable potential anticancer candidate that targets beta-catenin/Tcf-4 interaction.