Development of structure-based pharmacophore to target the β-catenin-TCF protein-protein interaction

beta-catenin concentration is methodically controlled by the Wnt signaling pathway, wherein mutations of this pathway can cause aberrant activation leading to an influx of beta-catenin, which is implicated in many cancers, specifically colon cancer. Targeting the beta-catenin-TCF interface has become a popular strategy because of its role in the Wnt signaling transduction pathway, but efforts to push a small-molecule inhibitor to clinical success have been futile. In our current study, we attempted to identify druggable hot spots at the beta-catenin-TCF interface by exploring plausible binding modes of a number of reported and chemically distinct inhibitors and defined their structure-based pharmacophore. Validation of our 4-feature pharmacophore hypothesis was carried out using another series of structure-related inhibitors with reported experimental data. Our hypothesis identified 73% of true actives with high enrichment of the most potent molecules in the test dataset. We speculate that our structure-based pharmacophore query may act as an in silico tool to rapidly screen small-molecule libraries for potentially new scaffolds to disrupt the beta-catenin-TCF protein-protein interaction. In addition, our pharmacophore successfully identified actives from a set of structurally similar inhibitors and, ultimately, may be applied as an adjunct tool in the hit-to-lead optimization process. [GRAPHICS]

Automated summary

The concentration of beta-catenin is controlled by the Wnt signaling pathway, with mutations in this pathway potentially causing aberrant activation associated with various cancers. Efforts to target the beta-catenin-TCF interface have not yet yielded clinical success, but a structure-based pharmacophore approach may provide a valuable tool for rapidly screening small-molecule libraries for disrupting protein-protein interactions.