Identification and structure-activity relationship of phenolic acyl hydrazones as selective agonists for the estrogen-related orphan nuclear receptors ERRbeta and ERRgamma.
The first small molecule agonists of the estrogen-related receptors have been identified. GSK4716 (3) and GSK9089 (4) show binding to ERRgamma with remarkable selectivity over the classical estrogen receptors. Notably, in cell-based reporter assays, 3 mimics the protein ligand PGC-1alpha in activation of human ERRbeta and ERRgamma.
Zuercher
William J
WJ
Discovery Research, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27707, USA. william.j.zuercher@gsk.com
Gaillard
Stéphanie
S
Orband-Miller
Lisa A
LA
Chao
Esther Y H
EY
Shearer
Barry G
BG
Jones
David G
DG
Miller
Aaron B
AB
Collins
Jon L
JL
McDonnell
Donald P
DP
Willson
Timothy M
TM
D001667:Binding, Competitive; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics; D031541:Fluorescence Resonance Energy Transfer; D017930:Genes, Reporter; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D018716:Molecular Mimicry; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000819:agonists* / Q000235:genetics; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000096:biosynthesis
D047629:Estrogen Receptor beta; D006360:Heat-Shock Proteins; D006834:Hydrazines; D008024:Ligands; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010636:Phenols; D011960:Receptors, Estrogen; D014157:Transcription Factors; C425824:estrogen receptor gamma