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

• Main 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
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Biological sciences; Biochemistry; Cancer
• Online Access: https://hdl.handle.net/10356/160682
• Institution: Nanyang Technological University

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.