Identification of novel estrogen receptor α antagonists

Dalei Shao, Thomas J. Berrodin, Eric Manas, Diane Hauze, Robert Powers, Ashok Bapat, Daniel Gonder, Richard C. Winneker, Donald E. Frail

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


We have identified novel estrogen receptor alpha (ERα) 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 ERα 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 ERα LBD complexed with a LxxLL peptide. All selected compounds effectively inhibited 17-β-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-β-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.

Original languageEnglish (US)
Pages (from-to)351-360
Number of pages10
JournalJournal of Steroid Biochemistry and Molecular Biology
Issue number4-5
StatePublished - Apr 2004


  • Antagonist
  • Coactivators
  • Estrogen receptor
  • SRC

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology


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