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

The
β-catenin/T-cell factor (Tcf) protein–protein
interaction (PPI) plays a critical role in the β-catenin signaling
pathway which is hyperactivated in many cancers and fibroses. Based
on compound 1, which was designed to target the Tcf4
G13ANDE17 binding site of β-catenin, extensive
structure–activity relationship studies have been conducted.
As a result, compounds 53 and 57 were found
to disrupt the β-catenin/Tcf PPI with the Ki values of 0.64 and 0.44 μM, respectively, and
exhibit good selectivity for β-catenin/Tcf over β-catenin/E-cadherin
and β-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/β-catenin
hyperactive cancer cells. Further cell-based studies indicated that 56 disrupted the β-catenin/Tcf PPI without affecting
the β-catenin/E-cadherin and β-catenin/APC PPIs, suppressed
transactivation of Wnt/β-catenin signaling in dose-dependent
manners, and inhibited migration and invasiveness of Wnt/β-catenin-dependent
cancer cells.