On the intractability of estrogen-related receptor alpha as a target for activation by small molecules.
The estrogen-related receptor alpha (ERRalpha) is a potential target for activation in the treatment of metabolic disease. To date, no small-molecule agonists of ERRalpha have been identified despite several high-throughput screening campaigns. We describe the synthesis and profiling of a small array of compounds designed on the basis of a previously reported agonist-bound crystal structure of the closely related receptor ERRgamma. The results suggest that ERRalpha may be intractable as a direct target for pharmacologic activation.
Hyatt
Stephen M
SM
Molecular Discovery Research Branch, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
Lockamy
Elizabeth L
EL
Stein
Rebecca A
RA
McDonnell
Donald P
DP
Miller
Aaron B
AB
Orband-Miller
Lisa A
LA
Willson
Timothy M
TM
Zuercher
William J
WJ
D001665:Binding Sites; D018360:Crystallography, X-Ray; D054314:Drug Inverse Agonism; D031541:Fluorescence Resonance Energy Transfer; D006367:HeLa Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000097983:ERRalpha Estrogen-Related Receptor
D006835:Hydrazones; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor