title: Identification of matrix metalloproteinase inhibitors by chemical arrays.
abstract: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade many extracellular matrix components and that have been implicated in the pathogenesis of various human diseases including cancer metastasis. Here, we screened MMP-9 inhibitors using photo-cross-linked chemical arrays, which can detect small-molecule ligand-protein interactions on a chip in a high-throughput manner. The array slides were probed sequentially with His-MMP-9, anti-His antibody, and a Cy5-labeled secondary antibody and then scanned with a microarray scanner. We obtained 27 hits among 24,275 compounds from the NPDepo library; 2 of the identified compounds (isoxazole compound 1 and naphthofluorescein) inhibited MMP-9 enzyme activity in vitro. We further explored 17 analogs of 1 and found that compound 18 had the strongest inhibitory activity. Compound 18 also inhibited other MMPs, including MMP-2, MMP-12, and MMP-13 and significantly inhibited cell migration in human fibrosarcoma HT1080 cells. These results suggest that 18 is a broad-spectrum MMP inhibitor.
authors.affiliation: a Antibiotics Laboratory , RIKEN , Saitama , Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawatani
authors.forename: Yukako
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.forename: Kaori
authors.initials: K
authors.lastname: Honda
authors.forename: Tomomi
authors.initials: T
authors.lastname: Sekine
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D055808:Drug Discovery; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005452:Fluoresceins / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006639:Histidine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D046228:Microarray Analysis; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D005452:Fluoresceins; C471213:His-His-His-His-His-His; D007555:Isoxazoles; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D054852:Small Molecule Libraries; C000601316:naphthofluorescein; D006639:Histidine; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12
keywords: chemical arrays; inhibitor; matrix metalloproteinase