Identification of novel estrogen receptor alpha antagonists.

We have identified novel estrogen receptor alpha (ERalpha) antagonists using both cell-based and computer-based virtual screening strategies. A mammalian two-hybrid screen was used to select compounds that disrupt the interaction between the ERalpha ligand binding domain (LBD) and the coactivator SRC-3. A virtual screen was designed to select compounds that ...
fit onto the LxxLL peptide-binding surface of the receptor, based on the X-ray crystal structure of the ERalpha LBD complexed with a LxxLL peptide. All selected compounds effectively inhibited 17-beta-estradiol induced coactivator recruitment with potency ranging from nano-molar to micromolar. However, in contrast to classical ER antagonists, these novel inhibitors poorly displace estradiol in the ER-ligand competition assay. Nuclear magnetic resonance (NMR) suggested direct binding of these compounds to the receptors pre-complexed with estradiol and further demonstrated that no estradiol displacement occurred. Partial proteolytic enzyme digestion revealed that, when compared with 17-beta-estradiol- and 4 hydroxy-tamoxifen (4-OHT) bound receptors, at least one of these compounds might induce a unique receptor conformation. These small molecules may represent new classes of ER antagonists, and may have the potential to provide an alternative for the current anti-estrogen therapy.
Mesh Terms:
Acetyltransferases, Animals, Antineoplastic Agents, Drug Evaluation, Preclinical, Estradiol, Estrogen Antagonists, Estrogen Receptor alpha, Histone Acetyltransferases, Humans, Hydroxytestosterones, Ligands, Nuclear Receptor Coactivator 3, Oncogene Proteins, Protein Binding, Protein Conformation, Receptors, Estrogen, Trans-Activators
J. Steroid Biochem. Mol. Biol.
Date: Apr. 01, 2004
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