Identification of SR8278, a synthetic antagonist of the nuclear heme receptor REV-ERB.
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.
Douglas
D
Kojetin
Yongjun
Y
Wang
Theodore M
TM
Kamenecka
Thomas P
TP
Burris
D001665:Binding Sites; D002478:Cells, Cultured; D056970:Co-Repressor Proteins / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005943:Gluconeogenesis; D057809:HEK293 Cells; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D056970:Co-Repressor Proteins; D018076:DNA, Complementary; D007546:Isoquinolines; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011480:Protease Inhibitors; C558456:SR 8278; D013876:Thiophenes; D006418:Heme