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 journalArticle

62 Citations (Scopus)

Abstract

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
Volume88
Issue number4-5
DOIs
StatePublished - Apr 1 2004

Fingerprint

Estrogen Receptor alpha
Estradiol
Ligands
Peptides
Conformations
Estrogen Receptor Antagonists
Digestion
Assays
Screening
Estrogens
Peptide Hydrolases
Magnetic Resonance Spectroscopy
Crystal structure
Nuclear magnetic resonance
X-Rays
X rays
Molecules

Keywords

  • Antagonist
  • Coactivators
  • Estrogen receptor
  • SRC

ASJC Scopus subject areas

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

Cite this

Identification of novel estrogen receptor α antagonists. / Shao, Dalei; Berrodin, Thomas J.; Manas, Eric; Hauze, Diane; Powers, Robert; Bapat, Ashok; Gonder, Daniel; Winneker, Richard C.; Frail, Donald E.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 88, No. 4-5, 01.04.2004, p. 351-360.

Research output: Contribution to journalArticle

Shao, D, Berrodin, TJ, Manas, E, Hauze, D, Powers, R, Bapat, A, Gonder, D, Winneker, RC & Frail, DE 2004, 'Identification of novel estrogen receptor α antagonists', Journal of Steroid Biochemistry and Molecular Biology, vol. 88, no. 4-5, pp. 351-360. https://doi.org/10.1016/j.jsbmb.2004.01.007
Shao, Dalei ; Berrodin, Thomas J. ; Manas, Eric ; Hauze, Diane ; Powers, Robert ; Bapat, Ashok ; Gonder, Daniel ; Winneker, Richard C. ; Frail, Donald E. / Identification of novel estrogen receptor α antagonists. In: Journal of Steroid Biochemistry and Molecular Biology. 2004 ; Vol. 88, No. 4-5. pp. 351-360.
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