title: Antiproliferation activity of a small molecule repressor of liver receptor homolog 1.
abstract: 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.
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Corzo
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Yelenis
authors.initials: Y
authors.lastname: Mari
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Chang
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Tanya
authors.initials: T
authors.lastname: Khan
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Dana
authors.initials: D
authors.lastname: Kuruvilla
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Philippe
authors.initials: P
authors.lastname: Nuhant
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Graham M
authors.initials: GM
authors.lastname: West
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: Derek R
authors.initials: DR
authors.lastname: Duckett
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: Departments of Molecular Therapeutics (C.A.C., Y.M., M.R.C., T.K., D.K., N.K., G.M.W., D.R.D., P.R.G.) and Chemistry (P.N., W.R.R.), Scripps Research Institute, Scripps Florida, Jupiter, Florida pgriffin@scripps.edu.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C431936:Nr5a2 protein, mouse; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear