GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbα.
The identification of nonporphyrin ligands for the orphan nuclear receptor Rev-erbα will enable studies of its role as a heme sensor and regulator of metabolic and circadian signaling. We describe the development of a biochemical assay measuring the interaction between Rev-erbα and a peptide from the nuclear receptor corepressor-1 (NCoR). The assay was utilized to identify a small molecule ligand for Rev-erbα, GSK4112 (1), that was competitive with heme. In cells, 1 profiled as a Rev-erbα agonist in cells to inhibit expression of the circadian target gene bmal1. In addition, 1 repressed the expression of gluconeogenic genes in liver cells and reduced glucose output in primary hepatocytes. Therefore, 1 is useful as a chemical tool to probe the function of Rev-erbα in transcriptional repression, regulation of circadian biology, and metabolic pathways. Additionally, 1 may serve as a starting point for design of Rev-erbα chemical probes with in vivo pharmacological activity.
Grant
Daniel
D
GlaxoSmithKline, Research Triangle Park, North Carolina 27707, USA.
Yin
Lei
L
Collins
Jon L
JL
Parks
Derek J
DJ
Orband-Miller
Lisa A
LA
Wisely
G Bruce
GB
Joshi
Shree
S
Lazar
Mitchell A
MA
Willson
Timothy M
TM
Zuercher
William J
WJ
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002478:Cells, Cultured; D002940:Circadian Rhythm; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D056971:Nuclear Receptor Co-Repressor 1 / Q000737:chemistry / Q000378:metabolism*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D025941:Protein Interaction Mapping / Q000379:methods*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism*; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism*
C572356:GSK4112; D056971:Nuclear Receptor Co-Repressor 1; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D010455:Peptides; D054852:Small Molecule Libraries; D013876:Thiophenes; D006418:Heme; D005998:Glycine