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]annulen-5-amine, binds to ERRα with high affinity but does not bind to either ERRβ or ERRγ.
All Science Journal Classification (ASJC) codes
- Drug Discovery
- ERRγ specific antagonists
- Estrogen-related receptor α(ERRα)
- Homogeneous time-resolved fluorescence (HTRF)
- Proliferator-activated receptor γ coactivator-1α (PGC-1α)