Targeting the Tcf4 G13ANDE17 binding site to selectively disrupt ß-catenin/T-cell factor protein-protein interactions.

ABSTRACT

Selective disruption of protein-protein interactions by small molecules is important for probing the structure and dynamic aspects of cellular network. It can also provide new therapeutic targets. ß-Catenin of the canonical Wnt signaling pathway uses the same positively charged groove to bind with T-cell factor (Tcf), cadherin, and adenomatous polysis coli (APC). The extravagant formation of ß-catenin/Tcf interactions drives the initiation and progression of many cancers and fibroses, while ß-catenin/cadherin and ß-catenin/APC interactions are essential for cell-cell adhesion and ß-catenin degradation. In this study, a selective binding site that can differentiate ß-catenin/Tcf, ß-catenin/cadherin, and ß-catenin/APC interactions was identified by alanine scanning and biochemical assays. A new peptidomimetic strategy that incorporates SiteMap and multiple-copy simultaneous search was used to design selective small-molecule inhibitors for ß-catenin/Tcf interactions. A potent inhibitor was discovered to bind with ß-catenin and completely disrupt ß-catenin/Tcf interactions. It also exhibits dual selectivity for ß-catenin/Tcf over ß-catenin/cadherin and ß-catenin/APC interactions in both biochemical and cell-based assays. This study provides a proof of concept for designing selective inhibitors for ß-catenin/Tcf interactions.