4WZV

Crystal structure of a hydroxamate based inhibitor EN140 in complex with the MMP-9 catalytic domain

Summary for 4WZV

• Entry DOI: 10.2210/pdb4wzv/pdb
• Related: 4H1Q 4H2E 4H3X 4H82 4HMA
• Descriptor: Matrix metalloproteinase-9,Matrix metalloproteinase-9, GLYCEROL, (2R)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-2-{[(4'-methoxybiphenyl-4-yl)sulfonyl](propan-2-yloxy)amino}butanamide, ... (11 entities in total)
• Functional Keywords: mmp9 inhibitor complex, thyroid hormone-binding protein, hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted, extracellular space, extracellular matrix : P14780
• Total number of polymer chains: 2
• Total formula weight: 38442.89

Authors

Stura, E.A.,Vera, L.,Cassar-Lajeunesse, E.,Nuti, E.,Dive, V.,Rossello, A. (deposition date: 2014-11-20, release date: 2015-08-26, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.65 Å)