Molecular docking-aided identification of small molecule inhibitors targeting ß-catenin-TCF4 interaction.
iScience
; 24(6): 102544, 2021 Jun 25.
Article
em En
| MEDLINE
| ID: mdl-34142050
ABSTRACT
Here we report a molecular docking-based approach to identify small molecules that can target the ß-catenin (ß-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of ß-cat using publicly available ß-cat protein crystal structures, and existing ß-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to ß-cat, of which 3 were identified to be effective against a Wnt-responsive luciferase reporter. In vitro functional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the ß-cat-TCF4 PPI. GB1874 also affected the proliferation and stemness of Wnt-addicted colorectal cancer (CRC) cells in vitro. Encouragingly, GB1874 inhibited the growth of CRC tumor xenografts in vivo, thus demonstrating its potential for further development into therapeutics against Wnt-associated cancer indications.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
IScience
Ano de publicação:
2021
Tipo de documento:
Article