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
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
PubMed ID: 15145444
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