A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression

Rajesh R. Nair, Hector Avila, Xujun Ma, Zhengxin Wang, Michelle Lennartz, Bryant G. Darnay, Douglas D. Boyd, Chunhong Yan

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Aberrant gene expression is one of the driving forces for cancer progression and is considered an ideal target for chemical intervention. Although emerging bioluminescence reporter systems allow high-throughput searches for small molecules regulatory for gene expression, frequent silencing of reporter genes by epigenetic mechanisms hinders wide application of this drug discovery strategy. Here we report a novel system that directs the integration of a promoter-reporter construct to an open chromosomal location by Flp-mediated homologous recombination, thereby overcoming reporter-gene silencing. Using this system, we have screened more than 8000 compounds in the DIVERSet chemical library for repressors of a matrix metalloproteinase-9 (MMP-9) promoter and identified 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD) inhibitory for MMP-9 gene expression. Consistent with this effect, MPBD inhibits MMP-9-dependent invasion of UMSCC-1 oral cancer cells, preosteoclast migration, and receptor activator of nuclear factor-κB ligand-induced osteoclast activity over concentration ranges that repressed MMP-9 expression. Mechanistic studies indicated that MPBD antagonizes AP-1 function by inhibiting its transactivation activity. We conclude that the Flp-mediated homologous recombination system to direct reporter integration into open chromatin regions represents a novel strategy allowing for the development of high-throughput systems screening for lead compounds targeting aberrant gene expression in cancer.

Original languageEnglish (US)
Pages (from-to)919-929
Number of pages11
JournalMolecular pharmacology
Issue number3
StatePublished - Mar 2008
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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