title: Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ.
abstract: The retinoic acid receptor-related receptors (RORs) are members of the nuclear receptor (NR) superfamily of transcription factors. Several NRs are still characterized as orphan receptors because ligands have not yet been identified for these proteins. Here, we describe the identification of a synthetic RORα/RORγ ligand, SR1078. SR1078 modulates the conformation of RORγ in a biochemical assay and activates RORα and RORγ driven transcription. Furthermore, SR1078 stimulates expression of endogenous ROR target genes in HepG2 cells that express both RORα and RORγ. Pharmacokinetic studies indicate that SR1078 displays reasonable exposure following injection into mice, and consistent with SR1078 functioning as a RORα/RORγ agonist, expression of two ROR target genes, glucose-6-phosphatase and fibroblast growth factor 21, were stimulated in the liver. Thus, we have identified the first synthetic RORα/γ agonist, and this compound can be utilized as a chemical tool to probe the function of these receptors both in vitro and in vivo.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.forename: Philippe
authors.initials: P
authors.lastname: Nuhant
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Monica A
authors.initials: MA
authors.lastname: Istrate
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000819:agonists*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists*; D005466:Fluorocarbons
chemical_list: D001549:Benzamides; D008024:Ligands; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C559087:SR 1078; D005466:Fluorocarbons