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

Michael J. Chisamore, Ralph T. Mosley, Sheng Jian Cai, Elizabeth T. Birzin, Gregory O'Donnell, Paul Zuck, Osvaldo Flores, James Schaeffer, Susan P. Rohrer, J. Don Chen, Hilary A. Wilkinson

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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]-5H dibenzo[a,d][7]annulen-5-amine, binds to ERRα with high affinity but does not bind to either ERRβ or ERRγ.

Original languageEnglish (US)
Pages (from-to)203-218
Number of pages16
JournalDrug Development Research
Volume69
Issue number4
DOIs
StatePublished - Jun 1 2008

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Keywords

  • ERRγ specific antagonists
  • Estrogen-related receptor α(ERRα)
  • Homogeneous time-resolved fluorescence (HTRF)
  • Proliferator-activated receptor γ coactivator-1α (PGC-1α)

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