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

Academic Article
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Overview

authors

  • Kojetin, Douglas
  • Wang, Y. J.
  • Kamenecka, Theodore
  • Burris, Thomas

publication date

  • February 2011

journal

  • ACS Chemical Biology  Journal

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.

subject areas

  • Binding Sites
  • Cells, Cultured
  • Co-Repressor Proteins
  • DNA, Complementary
  • Dose-Response Relationship, Drug
  • Gluconeogenesis
  • HEK293 Cells
  • Heme
  • Humans
  • Isoquinolines
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Polymerase Chain Reaction
  • Protease Inhibitors
  • Thiophenes
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Identity

PubMed Central ID

  • PMC3042041

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb1002575

PubMed ID

  • 21043485
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Additional Document Info

start page

  • 131

end page

  • 134

volume

  • 6

issue

  • 2

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