8Z61

Human beta-catenin crystal structure

Summary for 8Z61

• Entry DOI: 10.2210/pdb8z61/pdb
• Descriptor: Catenin beta-1 (1 entity in total)
• Functional Keywords: bcl9, beta-catenin, structural protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 60187.65

Authors

Tim, F. (deposition date: 2024-04-18, release date: 2024-05-08, Last modification date: 2024-08-21)

Primary citation

Zhu, W.,Liu, C.,Xi, K.,Li, A.,Shen, L.A.,Li, Y.,Jia, M.,He, Y.,Chen, G.,Liu, C.,Chen, Y.,Chen, K.,Sun, F.,Zhang, D.,Duan, C.,Wang, H.,Wang, D.,Zhao, Y.,Meng, X.,Zhu, D.
Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting beta-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells.
J.Med.Chem., 67:12485-12520, 2024

PubMed Abstract: Aberrant activation of the Wnt/β-catenin signaling is associated with tumor development, and blocking β-catenin/BCL9 is a novel strategy for oncogenic Wnt/β-catenin signaling. Herein, we presented two novel β-catenin variations and exposed conformational dynamics in several β-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting β-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of β-catenin. Among them, had a strong affinity for β-catenin ( = 82 nM), the most potent inhibitor reported. In addition, and not only activate T cells but also promote the antigen presentation of cDC1, showing robust antitumor efficacy in the CT26 model. Collectively, our study demonstrated a series of potent small-molecule inhibitors targeting β-catenin/BCL9, which can enhance antigen presentation and activate cDC1 cells, delivering a potential strategy for boosting innate and adaptive immunity to overcome immunotherapy resistance.

PubMed: 38912577
DOI: 10.1021/acs.jmedchem.3c02079

Experimental method

X-RAY DIFFRACTION (2.5 Å)