7ZRB

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

7ZRB の概要

• エントリーDOI: 10.2210/pdb7zrb/pdb
• 分子名称: Catenin beta-1, 4-bromanyl-~{N}-(3-pyridin-2-ylphenyl)benzenesulfonamide (3 entities in total)
• 機能のキーワード: beta-catenin, colon cancer, wnt pathway, cell adhesion
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 118345.85

構造登録者

Capelli, D.,Pochetti, G.,Montanari, R. (登録日: 2022-05-04, 公開日: 2023-05-17, 最終更新日: 2024-02-07)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.434 Å)