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Biosci Biotechnol Biochem. 2015;79(10):1597-602. doi: 10.1080/09168451.2015.1045829. Epub 2015 May 19.

Identification of matrix metalloproteinase inhibitors by chemical arrays.

Author information

1
a Antibiotics Laboratory , RIKEN , Saitama , Japan.

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.

KEYWORDS:

chemical arrays; inhibitor; matrix metalloproteinase

PMID:
25988721
DOI:
10.1080/09168451.2015.1045829
[Indexed for MEDLINE]

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