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

Douglas Kojetin, Yongjun Wang, Theodore M. Kamenecka, Thomas P. Burris

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)131-134
Number of pages4
JournalACS Chemical Biology
Volume6
Issue number2
DOIs
StatePublished - Feb 18 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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