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

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

iScience

10.1016/j.isci.2021.102544

http://dx.doi.org/10.1016/j.isci.2021.102544

Joo-Leng Low, Weina Du, Tenzin Gocha, Gokce Oguz, Xiaoqian Zhang, Ming Wei Chen, Srdan Masirevic, Daniel Guo Rong Yim, Iain Bee Huat Tan, Adaikalavan Ramasamy, Hao Fan, Ramanuj DasGupta

Multidisciplinary

15 May 2021

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

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

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

https://oar.a-star.edu.sg/communities-collections/articles/18203

2589-0042

Institute of Molecular and Cell Biology

https://doi.org/10.1016/j.isci.2021.102544