摘要：SummaryHere we report a molecular docking-based approach to identify small molecules that can target the β-catenin (β-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of β-cat using publicly available β-cat protein crystal structures, and existing β-cat-TCF4 interaction inhibitors as the training set. Using our computational model to anin silicoscreen predicted 27 compounds as good binders to β-cat, of which 3 were identified to be effective against a Wnt-responsive luciferase reporter.In vitrofunctional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the β-cat-TCF4 PPI. GB1874 also affected the proliferation and stemness of Wnt-addicted colorectal cancer (CRC) cellsin vitro. Encouragingly, GB1874 inhibited the growth of CRC tumor xenograftsin vivo, thus demonstrating its potential for further development into therapeutics against Wnt-associated cancer indications.Graphical abstractDisplay OmittedHighlights•A computational docking model for β-catenin was developed and optimized.•The model was trained using protein crystal structures and known inhibitor compounds.•Compound GB1874 was identified byin silicoscreening and functionally validated.•GB1874 inhibited colon cancer growthin vitroandin vivoby blocking Wnt activity.Pharmacology; Biochemistry; Structural biology; Cancer; Omics
