RT Journal Article SR Electronic T1 A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 919 OP 929 DO 10.1124/mol.107.042606 VO 73 IS 3 A1 Rajesh R. Nair A1 Hector Avila A1 Xujun Ma A1 Zhengxin Wang A1 Michelle Lennartz A1 Bryant G. Darnay A1 Douglas D. Boyd A1 Chunhong Yan YR 2008 UL http://molpharm.aspetjournals.org/content/73/3/919.abstract 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