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 since 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.

The Identification of Naturally Occurring Neoruscogenin as a Bioavailable, Potent, and High-Affinity Agonist of the Nuclear Receptor RORα (NR1F1)

“…In contrast, reporter activity was only minimally induced in COS7 cells that expressed the Gal4-DBD construct. The capacity of neoruscogenin to induce RORα target gene expression in the natural chromatin context was then demonstrated in HepG2 cells, where the expression of G6Pase and Bmal1, both well-established RORα target genes, 14,18,22 was significantly induced upon neoruscogenin treatment (Fig. 3C).…”

“…12,13 Subsequently, 7-oxygenated sterols (7α-hydroxycholesterol, 7β-hydroxycholesterol, 7-ketocholesterol) and (24S)-hydroxycholesterol were identified as novel RORα ligands, with comparable nanomolar binding affinities, 14,15 and recently the structures of synthetic RORα ligands, based on either the benzenesulfonamide or thiourea scaffolds, have been published. [16][17][18] However, no potent and bioavailable ligands are available to date to address important questions about the complex biology of the RORα receptor in vivo. We demonstrate in this work that less conventional approaches, such as the identification of receptor ligands starting from a natural product library of plant extract fractions, are an efficient and effective method to identify potent and bioavailable pharmacological probes to be used for orphan target validation studies.…”

The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis

“…In WT mice, 7␤-hydroxycholesterol, a ROR␣ antagonist (47), decreased the incorporation of pyruvate into TG and simultaneously increased the FFA/glycerol release in the medium. On the contrary, SR1078, a ROR␣ agonist (46), did the opposite. It had no effect on the adipose tissue of ROR sg/sg mice, thus confirming the specific involvement of ROR␣ in the modulation of FFA homeostasis via glyceroneogenesis in adipose tissue.…”

Increasing Human Th17 Differentiation through Activation of Orphan Nuclear Receptor Retinoid Acid-Related Orphan Receptor γ (RORγ) by a Class of Aryl Amide Compounds

“…Kumar et al (2010) discovered synthetic compounds that not only behave as ligands to ROR␣ and ROR␥ but also suppress their transcriptional activities. A nonspecific ROR␥ synthetic agonist, SR1078, was identified by Wang et al (2010a) but with a low potency at ϳ10 M. In the course of compound screening looking for small-molecule inhibitors of ROR␥, we fortuitously discovered small-molecule compounds that are capable of activating ROR␥ with ϳ0.1 M potency, up to 100-fold more potent than N- (4-(1,1,1,3,3,3-hexafluoro-2-hydroxypro-pan-2-yl)phenyl)-4-(trifluoromethyl)benzamide (SR1078). These agonists can be used as surrogate ligands in screening assays and may greatly assist the development of selective ROR␥ antagonists.…”