PT  - JOURNAL ARTICLE
AU  - Cesar A. Corzo
AU  - Yelenis Mari
AU  - Mi Ra Chang
AU  - Tanya Khan
AU  - Dana Kuruvilla
AU  - Philippe Nuhant
AU  - Naresh Kumar
AU  - Graham M. West
AU  - Derek R. Duckett
AU  - William R. Roush
AU  - Patrick R. Griffin
TI  - Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1
AID  - 10.1124/mol.114.095554
DP  - 2015 Feb 01
TA  - Molecular Pharmacology
PG  - 296--304
VI  - 87
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/87/2/296.short
4100  - http://molpharm.aspetjournals.org/content/87/2/296.full
SO  - Mol Pharmacol2015 Feb 01; 87
AB  - The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid dilauroylphosphatidylcholine activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic nonphospholipid small molecule repressor of LRH-1, SR1848 (6-[4-(3-chlorophenyl)piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione). In cotransfection studies, SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1 dose dependently reduced the expression of cyclin-D1 and -E1, resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated after transfection of cells with small-interfering RNA targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 that impacts expression of genes involved in proliferation in LRH-1–expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.