4XCT
Crystal structure of a hydroxamate based inhibitor ARP101 (EN73) in complex with the MMP-9 catalytic domain.
Summary for 4XCT
| Entry DOI | 10.2210/pdb4xct/pdb |
| Descriptor | 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) |
| Functional Keywords | inhibitor-complex, metalloprotease, hydrolase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 18965.99 |
| Authors | Stura, E.A.,Tepshi, L.,Nuti, E.,Dive, V.,Cassar-Lajeunesse, E.,Vera, L.,Rossello, A. (deposition date: 2014-12-18, release date: 2015-04-22, 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 Cited by 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: 26263024DOI: 10.1021/acs.jmedchem.5b00367 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.3 Å) |
Structure validation
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