PT - JOURNAL ARTICLE AU - Nair, Rajesh R. AU - Avila, Hector AU - Ma, Xujun AU - Wang, Zhengxin AU - Lennartz, Michelle AU - Darnay, Bryant G. AU - Boyd, Douglas D. AU - Yan, Chunhong TI - A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression AID - 10.1124/mol.107.042606 DP - 2008 Mar 01 TA - Molecular Pharmacology PG - 919--929 VI - 73 IP - 3 4099 - http://molpharm.aspetjournals.org/content/73/3/919.short 4100 - http://molpharm.aspetjournals.org/content/73/3/919.full SO - Mol Pharmacol2008 Mar 01; 73 AB - 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. The American Society for Pharmacology and Experimental Therapeutics