Molecular docking-aided identification of small molecule inhibitors targeting β-catenin-TCF4 interaction

Here we report a molecular docking-based approach to identify small molecules that can target the beta-catenin (beta-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of b-cat using publicly available beta-cat protein crystal structures, and existing beta-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to beta-cat, of which 3 were identified to be effective against aWnt-responsive luciferase reporter. In vitro functional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the beta-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.

Automated summary

A molecular docking-based approach was used to identify small molecules targeting the beta-catenin (beta-cat)-TCF4 protein-protein interaction (PPI) in the nuclear Wnt signaling pathway. In vitro experiments confirmed that GB1874 is an effective inhibitor of the Wnt pathway, impacting proliferation and stemness in colorectal cancer cells. In vivo studies demonstrated that GB1874 inhibited the growth of colorectal cancer tumor xenografts, showing potential for therapeutic development against Wnt-associated cancer indications.