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Title: Molecular docking-aided identification of small molecule inhibitors targeting β-catenin-TCF4 interaction
Authors: Low, Joo-Leng
Du, Weina
Gocha, Tenzin
Oguz, Gokce
Zhang, Xiaoqian
Chen, Ming Wei
Masirevic, Srdan
Yim, Daniel Guo Rong
Tan, Iain Bee Huat
Ramasamy, Adaikalavan
Fan, Hao
DasGupta, Ramanuj
Keywords: Science::Biological sciences
Issue Date: 2021
Source: Low, J., 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-.
Journal: iScience
Abstract: Here 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 an in silico screen predicted 27 compounds as good binders to β-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 β-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.
ISSN: 2589-0042
DOI: 10.1016/j.isci.2021.102544
Schools: School of Biological Sciences 
Research Centres: BioSciences Research Centre 
Rights: © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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