SR1078

SR1078 is an agonist of retinoic acid receptor-related orphan receptor (ROR) RORα and RORγ with IC50 values of both 1-3 µM [1].

RORα and RORγ are two members of nuclear receptor superfamily, which possesses a highly conserved DNA-binding and a ligand-binding domain. These two receptors are considered to play important roles in the regulation of metabolism and the function of immune system [1].

SR1078 is a selective RORα and RORγ agonist, which activate RORα and RORγ directed transcription via inducing conformational changes [1].

SR1078 selectively targets on RORα and RORγ as an agonist but not on LXR and FXR [1]. It was shown that SR1078 was able to stimulate ROR activity and subsequent ROR-directed mRNA expression. When HepG2 cells were treated with SR1078 for 24h, the ROR directed reporter gene FG21 mRNA level was increased by 3-fold, while another reporter gene G6Pase was increased by 2-fold [1].

In mouse model, i.p. injection of 10 mg/kg SR1078 for 1 hr resulted in 3.6 μM plasma concentration., and after 8 hr the concentration still sustained at 800 nM. i.p. injection of 10 mg/kg SR1078 for 2 hr resulted in significantly increased level of mRNA of reporter gene G6Pase and FG21 [1].

Reference:
[1] Wang Y et al. , Identification of a Synthetic Agonist for the Orphan Nuclear Receptors RORα and RORγ, SR1078. ACS Chem Biol., 2010, 5(11): 1029-1034.

Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORalpha and RORgamma.[Pubmed:20735016]

ACS Chem Biol. 2010 Nov 19;5(11):1029-34.

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 RORalpha/RORgamma ligand, SR1078. SR1078 modulates the conformation of RORgamma in a biochemical assay and activates RORalpha and RORgamma driven transcription. Furthermore, SR1078 stimulates expression of endogenous ROR target genes in HepG2 cells that express both RORalpha and RORgamma. Pharmacokinetic studies indicate that SR1078 displays reasonable exposure following injection into mice, and consistent with SR1078 functioning as a RORalpha/RORgamma 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 RORalpha/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.

Regulation of p53 stability and apoptosis by a ROR agonist.[Pubmed:22509368]

PLoS One. 2012;7(4):e34921.

Activation of p53 function leading to cell-cycle arrest and/or apoptosis is a promising strategy for development of anti-cancer therapeutic agents. Here, we describe a novel mechanism for stabilization of p53 protein expression via activation of the orphan nuclear receptor, RORalpha. We demonstrate that treatment of cancer cells with a newly described synthetic ROR agonist, SR1078, leads to p53 stabilization and induction of apoptosis. These data suggest that synthetic ROR agonists may hold utility in the treatment of cancer.