Biophysical Survey of Small-Molecule ß-Catenin Inhibitors: A Cautionary Tale.
J Med Chem
; 65(10): 7246-7261, 2022 05 26.
Article
em En
| MEDLINE
| ID: mdl-35581674
ABSTRACT
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. ß-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 ß-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 ß-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 ß-catenin. While shedding doubts on their reported mode of action, this study also reaffirms ß-catenin as a prominent target in drug discovery.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Beta Catenina
/
Bibliotecas de Moléculas Pequenas
/
Via de Sinalização Wnt
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article