Biophysical Survey of Small-Molecule β‑Catenin Inhibitors: A Cautionary Tale

The canonical Wingless-related
integration site signaling pathway
plays a critical role in human physiology, and its dysregulation can
lead to an array of diseases. β-Catenin is a multifunctional
protein within this pathway and an attractive yet challenging therapeutic
target, most notably in oncology. This has stimulated the search for
potent small-molecule inhibitors binding directly to the β-catenin
surface to inhibit its protein–protein interactions and downstream
signaling. Here, we provide an account of the claimed (and some putative)
small-molecule ligands of β-catenin from the literature. Through
in silico analysis, we show that most of these molecules contain promiscuous
chemical substructures notorious for interfering with screening assays.
Finally, and in line with this analysis, we demonstrate using orthogonal
biophysical techniques that none of the examined small molecules bind
at the surface of β-catenin. While shedding doubts on their
reported mode of action, this study also reaffirms β-catenin
as a prominent target in drug discovery.