7ZRB

Crystal structure of Beta-catenin Armadillo repeats domain in complex with the inhibitor RS6452

Summary for 7ZRB

• Entry DOI: 10.2210/pdb7zrb/pdb
• Descriptor: Catenin beta-1, 4-bromanyl-~{N}-(3-pyridin-2-ylphenyl)benzenesulfonamide (3 entities in total)
• Functional Keywords: beta-catenin, colon cancer, wnt pathway, cell adhesion
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 118345.85

Authors

Capelli, D.,Pochetti, G.,Montanari, R. (deposition date: 2022-05-04, release date: 2023-05-17, Last modification date: 2024-02-07)

Primary citation

Nalli, M.,Di Magno, L.,Wen, Y.,Liu, X.,D'Ambrosio, M.,Puxeddu, M.,Parisi, A.,Sebastiani, J.,Sorato, A.,Coluccia, A.,Ripa, S.,Di Pastena, F.,Capelli, D.,Montanari, R.,Masci, D.,Urbani, A.,Naro, C.,Sette, C.,Orlando, V.,D'Angelo, S.,Biagioni, S.,Bigogno, C.,Dondio, G.,Pastore, A.,Stornaiuolo, M.,Canettieri, G.,Liu, T.,Silvestri, R.,La Regina, G.
Novel N -(Heterocyclylphenyl)benzensulfonamide Sharing an Unreported Binding Site with T-Cell Factor 4 at the beta-Catenin Armadillo Repeats Domain as an Anticancer Agent.
Acs Pharmacol Transl Sci, 6:1087-1103, 2023

PubMed Abstract: Despite intensive efforts, no inhibitors of the Wnt/β-catenin signaling pathway have been approved so far for the clinical treatment of cancer. We synthesized novel -(heterocyclylphenyl)benzenesulfonamides as β-catenin inhibitors. Compounds - showed strong inhibition of the luciferase activity. Compounds and inhibited the MDA-MB-231, HCC1806, and HCC1937 TNBC cells. Compound induced in vitro cell death in SW480 and HCT116 cells and in vivo tumorigenicity of a human colorectal cancer line HCT116. In a co-immunoprecipitation study in HCT116 cells transfected with Myc-tagged T-cell factor 4 (Tcf-4), compound abrogated the association between β-catenin and Tcf-4. The crystallographic analysis of the β-catenin Armadillo repeats domain revealed that compound and Tcf-4 share a common binding site within the hotspot binding region close to Lys508. To our knowledge, compound is the first small molecule ligand of this region to be reported. These results highlight the potential of this novel class of β-catenin inhibitors as anticancer agents.

PubMed: 37470018
DOI: 10.1021/acsptsci.3c00092

Experimental method

X-RAY DIFFRACTION (3.434 Å)