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[摘要]：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 ROR alpha/ROR gamma-ligand, SR1078. SR1078 modulates the conformation of ROR gamma in a biochemical assay and activates ROR alpha and ROR gamma driven transcription. Furthermore, SR1078 stimulates expression of endogenous ROR target genes in HepG2 cells that express both ROR alpha and ROR gamma. PharmacokinetiC studies indicate that SR1078 displays reasonable exposure following injection into mice, and consistent. with SR1078 functioning as a ROR alpha/ROR-y agonist, expression of two ROR target genes, glucose-6-phosphatose and fibroblast growth factor 21, were stimulated in the liver. Thus, we have identified the first synthetic ROR alpha/gamma agonist, and this compound can be utilized as a chemical tool to probe the function of these receptors both In vitro and In vivo. |
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