Journal
ACS CHEMICAL BIOLOGY
Volume 6, Issue 2, Pages 131-134Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb1002575
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Funding
- NIH [DK080201]
- National Institutes of Health (NIH) Molecular Library Screening Center Network (MLSCN) [U54MH074404]
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REV-ERB alpha is a member of the nuclear receptor superfamily that functions as a receptor for the porphoryin heme. REV-ERB alpha suppresses transcription of its target genes in a heme-dependent manner. Recently, the first nonporphyrin synthetic ligand for REV-ERB alpha, 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-ERB alpha-dependent repression in a cotransfection assay. Additionally, whereas GSK4112 suppresses the expression of REV-ERB alpha 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.
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