Biophysical Survey of Small-Molecule?-Catenin Inhibitors: ACautionary Tale

The canonical Wingless-related integration site signal-ing pathway plays a critical role in human physiology, and itsdysregulation can lead to an array of diseases.beta-Catenin is amultifunctional protein within this pathway and an attractive yetchallenging therapeutic target, most notably in oncology. This hasstimulated the search for potent small-molecule inhibitors bindingdirectly to the beta-catenin surface to inhibit its protein-proteininteractions and downstream signaling. Here, we provide an accountof the claimed (and some putative) small-molecule ligands of beta-catenin from the literature. Through in silico analysis, we show thatmost of these molecules contain promiscuous chemical substructuresnotorious for interfering with screening assays. Finally, and in linewith this analysis, we demonstrate using orthogonal biophysicaltechniques that none of the examined small molecules bind at the surface of beta-catenin. While shedding doubts on their reportedmode of action, this study also reaffirms beta-catenin as a prominent target in drug discovery

Automated summary

This study focuses on small-molecule ligands of β-catenin as therapeutic targets in the Wnt signaling pathway. Through computational analysis and biophysical techniques, it is shown that these small molecules do not bind to the surface of β-catenin. This raises doubts about their reported mode of action and reaffirms the significance of β-catenin in drug discovery.