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ACS Chem Biol. 2011 Feb 18;6(2):131-4. doi: 10.1021/cb1002575. Epub 2010 Nov 10.

Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB.

Abstract

REV-ERBα is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERBα suppresses transcription of its target genes in a heme-dependent manner. Recently, the first nonporphyrin synthetic ligand for REV-ERBα, GSK4112, was designed, and it mimics the action of heme acting as agonist. Here, we report the identification of the first REV-ERB antagonist, SR8278. SR8278 is structurally similar to the agonist but blocks the ability of the GSK4112 to enhance REV-ERBα-dependent repression in a cotransfection assay. Additionally, whereas GSK4112 suppresses the expression of REV-ERBα target genes involved in gluconeogenesis, SR8278 stimulates the expression of these genes. Thus, SR8278 represents a unique chemical tool for probing REV-ERB function and may serve as a point for initiation of further optimization to develop REV-ERB antagonists with the ability to explore circadian and metabolic functions.

PMID:
21043485
PMCID:
PMC3042041
DOI:
10.1021/cb1002575
[Indexed for MEDLINE]
Free PMC Article

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