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

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Molecular docking-aided identification of small molecule inhibitors targeting β-catenin-TCF4 interaction
Title:
Molecular docking-aided identification of small molecule inhibitors targeting β-catenin-TCF4 interaction
Other Titles:
iScience
Publication Date:
15 May 2021
Citation:
Low, J.-L., Du, W., Gocha, T., Oguz, G., Zhang, X., Chen, M. W., Masirevic, S., Yim, D. G. R., Tan, I. B. H., Ramasamy, A., Fan, H., & DasGupta, R. (2021). Molecular docking-aided identification of small molecule inhibitors targeting β-catenin-TCF4 interaction. IScience, 24(6), 102544. https://doi.org/10.1016/j.isci.2021.102544
Abstract:
Here we report a molecular docking-based approach to identify small molecules that can target the b-catenin (b-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 b-cat protein crystal structures, and existing b-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to b-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 b-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.
License type:
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Funding Info:
This research / project is supported by the National Institutes of Health / National Cancer Institute - NIH RO1 grant funding program
Grant Reference no. : 1R01CA155125-01

This research is supported by core funding from: BMRC
Grant Reference no. : NA

This research / project is supported by the National Research Foundation (NRF) - Competitive Research Program
Grant Reference no. : NRF-CRP-2017-02
Description:
ISSN:
2589-0042