Optimization of Peptidomimetics as Selective Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction

The beta-catenin/T-cell factor (Tcf) protein-protein interaction (PPI) plays a critical role in the beta-catenin signaling pathway which is hyperactivated in many cancers and fibroses. Based on compound 1, which was designed to target the Tcf4 G(13)ANDE(17) binding site of beta-catenin, extensive structure-activity relationship studies have been conducted. As a result, compounds 53 and 57 were found to disrupt the beta-catenin/Tcf PPI with the K-i values of 0.64 and 0.44 mu M, respectively, and exhibit good selectivity for beta-catenin/Tcf over beta-catenin/E-cadherin and beta-catenin/adenomatous polyposis coli (APC) PPIs. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) cell viability assays revealed that 56, the ethyl ester of 53, was more potent than 53 in inhibiting viability of most of the Wnt/beta-catenin hyperactive cancer cells. Further cell-based studies indicated that 56 disrupted the beta-catenin/Tcf PPI without affecting the beta-catenin/E-cadherin and beta-catenin/APC PPIs, suppressed transactivation of Wnt/beta-catenin signaling in dose-dependent manners, and inhibited migration and invasiveness of Wnt/beta-catenin-dependent cancer cells.