Identification of small molecule estrogen-related receptor α-specific antagonists and homology modeling to predict the molecular determinants as the basis for selectivity over ERRβ and ERRγ

• Published in: Drug development research Vol. 69; no. 4; pp. 203 - 218
• Main Authors: Chisamore, Michael J., Mosley, Ralph T., Cai, Sheng-Jian, Birzin, Elizabeth T., O'Donnell, Gregory, Zuck, Paul, Flores, Osvaldo, Schaeffer, James, Rohrer, Susan P., Don Chen, J., Wilkinson, Hilary A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.06.2008
• Subjects: ERRα specific antagonists; estrogen-related receptor α (ERRα); homogeneous time-resolved fluorescence (HTRF); Proliferator-activated Receptor γ Coactivator-1α (PGC-1α)
• DOI: 10.1002/ddr.20246
• ISSN: 0272-4391

The estrogen‐related receptor α (ERRα) was one of the first orphan receptors identified through a search for genes encoding proteins related to the steroid nuclear receptor, Estrogen Receptor α (ERα). The physiological role of ERRα has not yet been established nor has a natural ligand been elucidated. Importantly, research indicates that ERRα may be a novel drug target to treat breast cancer and/or metabolic disorders. A homogeneous time‐resolved fluorescence (HTRF) assay has been developed to screen for ERRα‐specific antagonists. This assay uses the ERR ligand binding domain and the coactivator interaction domain of Proliferator‐activated Receptor γ Coactivator‐1α (PGC‐1α) to examine the ability of compounds to antagonize the constitutive interaction between ERRα and the coactivator. A dissociation‐enhanced lanthanide fluorescence immunoassay (DELFIA) was also created to counter screen compounds identified in the HTRF screen. Here we report the discovery of high‐affinity ERRα subtype selective antagonists. Additionally, a homology model of ERRα in an antagonist conformation has been developed and after subsequent docking studies, we offer a model showing the molecular determinants that suggest why our novel tri‐cyclic antagonist, N‐[(2Z)‐3‐(4,5‐dihydro‐1,3‐thiazol‐2‐yl)‐1,3‐thiazolidin‐2‐yl idene]‐5 H dibenzo[a,d][7]annulen‐5‐amine, binds to ERRα with high affinity but does not bind to either ERRβ or ERRγ. Drug Dev Res 69:203–218, 2008. © 2008 Wiley‐Liss, Inc.