Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORα and RORγ

被引：132

作者：

Wang, Yongjun ^{[1
]}

Kumar, Naresh ^{[1
]}

Nuhant, Philippe ^{[1
]}

Cameron, Michael D. ^{[1
]}

Istrate, Monica A. ^{[1
]}

Roush, William R. ^{[1
]}

Griffin, Patrick R. ^{[1
]}

Burris, Thomas P. ^{[1
]}

机构：

[1] Scripps Res Inst, Jupiter, FL 33458 USA

来源：

ACS CHEMICAL BIOLOGY | 2010年 / 5卷 / 11期

基金：

美国国家卫生研究院;

关键词：

REV-ERB-ALPHA; X-RECEPTOR; LIGAND; DIFFERENTIATION; CHOLESTEROL; METABOLISM; T0901317; ANGSTROM; HEME;

D O I：

10.1021/cb100223d

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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.

引用

页码：1029 / 1034

页数：6

共 22 条

[1] Retinoid X receptor is a nonsilent major contributor to vitamin D receptor-mediated transcriptional activation [J].