4XCT

Crystal structure of a hydroxamate based inhibitor ARP101 (EN73) in complex with the MMP-9 catalytic domain.

4XCT の概要

• エントリーDOI: 10.2210/pdb4xct/pdb
• 分子名称: Matrix metalloproteinase-9,Matrix metalloproteinase-9, (2~{R})-3-methyl-~{N}-oxidanylidene-2-[(4-phenylphenyl)sulfonyl-propan-2-yloxy-amino]butanamide, ZINC ION, ... (10 entities in total)
• 機能のキーワード: inhibitor-complex, metalloprotease, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18965.99

構造登録者

Stura, E.A.,Tepshi, L.,Nuti, E.,Dive, V.,Cassar-Lajeunesse, E.,Vera, L.,Rossello, A. (登録日: 2014-12-18, 公開日: 2015-04-22, 最終更新日: 2024-01-10)

主引用文献

Nuti, E.,Cantelmo, A.R.,Gallo, C.,Bruno, A.,Bassani, B.,Camodeca, C.,Tuccinardi, T.,Vera, L.,Orlandini, E.,Nencetti, S.,Stura, E.A.,Martinelli, A.,Dive, V.,Albini, A.,Rossello, A.
N-O-Isopropyl Sulfonamido-Based Hydroxamates as Matrix Metalloproteinase Inhibitors: Hit Selection and in Vivo Antiangiogenic Activity.
J.Med.Chem., 58:7224-7240, 2015

PubMed Abstract: Matrix metalloproteinases (MMPs) have been shown to be involved in tumor-induced angiogenesis. In particular, MMP-2, MMP-9, and MMP-14 have been reported to be crucial for tumor angiogenesis and the formation of metastasis, thus becoming attractive targets in cancer therapy. Here, we report our optimization effort to identify novel N-isopropoxy-arylsulfonamide hydroxamates with improved inhibitory activity toward MMP-2, MMP-9, and MMP-14 with respect to the previously discovered compound 1. A new series of hydroxamates was designed, synthesized, and tested for their antiangiogenic activity using in vitro assays with human umbilical vein endothelial cells (HUVECs). A nanomolar MMP-2, MMP-9, and MMP-14 inhibitor was identified, compound 3, able to potently inhibit angiogenesis in vitro and also in vivo in the matrigel sponge assay in mice. Finally, X-ray crystallographic and docking studies were conducted for compound 3 in order to investigate its binding mode to MMP-9 and MMP-14.

PubMed: 26263024
DOI: 10.1021/acs.jmedchem.5b00367

実験手法

X-RAY DIFFRACTION (1.3 Å)