Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ

Yongjun Wang, Naresh Kumar, Philippe Nuhant, Michael D. Cameron, Monica A. Istrate, William R. Roush, Patrick R. Griffin, Thomas P. Burris

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1029-1034
Number of pages6
JournalACS Chemical Biology
Volume5
Issue number11
DOIs
StatePublished - Nov 19 2010

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Orphan Nuclear Receptors
Artificial Receptors
Genes
Ligands
Glucose-6-Phosphatase
Retinoic Acid Receptors
Pharmacokinetics
Hep G2 Cells
Transcription
Cytoplasmic and Nuclear Receptors
Liver
Conformations
Assays
Transcription Factors
SR 1078
Injections
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Wang, Y., Kumar, N., Nuhant, P., Cameron, M. D., Istrate, M. A., Roush, W. R., ... Burris, T. P. (2010). Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. ACS Chemical Biology, 5(11), 1029-1034. https://doi.org/10.1021/cb100223d

Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. / Wang, Yongjun; Kumar, Naresh; Nuhant, Philippe; Cameron, Michael D.; Istrate, Monica A.; Roush, William R.; Griffin, Patrick R.; Burris, Thomas P.

In: ACS Chemical Biology, Vol. 5, No. 11, 19.11.2010, p. 1029-1034.

Research output: Contribution to journalArticle

Wang, Y, Kumar, N, Nuhant, P, Cameron, MD, Istrate, MA, Roush, WR, Griffin, PR & Burris, TP 2010, 'Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ', ACS Chemical Biology, vol. 5, no. 11, pp. 1029-1034. https://doi.org/10.1021/cb100223d
Wang, Yongjun ; Kumar, Naresh ; Nuhant, Philippe ; Cameron, Michael D. ; Istrate, Monica A. ; Roush, William R. ; Griffin, Patrick R. ; Burris, Thomas P. / Identification of SR1078, a synthetic agonist for the orphan nuclear receptors RORα and RORγ. In: ACS Chemical Biology. 2010 ; Vol. 5, No. 11. pp. 1029-1034.
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