title: Small-molecule "BRCA1-mimetics" are antagonists of estrogen receptor-α.
abstract: BACKGROUND
  Resistance to conventional antiestrogens is a major cause of treatment failure and, ultimately, death in breast cancer.
  
  
  OBJECTIVE
  The objective of the study was to identify small-molecule estrogen receptor (ER)-α antagonists that work differently from tamoxifen and other selective estrogen receptor modulators.
  
  
  METHODS
  Based on in silico screening of a pharmacophore database using a computed model of the BRCA1-ER-α complex (with ER-α liganded to 17β-estradiol), we identified a candidate group of small-molecule compounds predicted to bind to a BRCA1-binding interface separate from the ligand-binding pocket and the coactivator binding site of ER-α. Among 40 candidate compounds, six inhibited estradiol-stimulated ER-α activity by at least 50% in breast carcinoma cells, with IC50 values ranging between 3 and 50 μM. These ER-α inhibitory compounds were further studied by molecular and cell biological techniques.
  
  
  RESULTS
  The compounds strongly inhibited ER-α activity at concentrations that yielded little or no nonspecific toxicity, but they produced only a modest inhibition of progesterone receptor activity. Importantly, the compounds blocked proliferation and inhibited ER-α activity about equally well in antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Representative compounds disrupted the interaction of BRCA1 and ER-α in the cultured cells and blocked the interaction of ER-α with the estrogen response element. However, the compounds had no effect on the total cellular ER-α levels.
  
  
  CONCLUSIONS
  These findings suggest that we have identified a new class of ER-α antagonists that work differently from conventional antiestrogens (eg, tamoxifen and fulvestrant).
authors.affiliation: Departments of Oncology (Y.M., Y.T., A.P., R.C., E.E., S.G., S.N., E.D.O., M.L.B., E.M.R.), Biochemistry and Molecular and Cellular Biology (E.M.R.), Radiation Medicine (E.M.R.), and Center for Drug Discovery (Y.T., E.E., S.G., E.D.O., M.L.B.), Georgetown University School of Medicine, Washington, DC 20057.
authors.forename: Yongxian
authors.initials: Y
authors.lastname: Ma
authors.forename: York
authors.initials: Y
authors.lastname: Tomita
authors.forename: Anju
authors.initials: A
authors.lastname: Preet
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Erikah
authors.initials: E
authors.lastname: Englund
authors.forename: Scott
authors.initials: S
authors.lastname: Grindrod
authors.forename: Shyam
authors.initials: S
authors.lastname: Nathan
authors.forename: Eliseu
authors.initials: E
authors.lastname: De Oliveira
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Eliot M
authors.initials: EM
authors.lastname: Rosen
mesh_terms: D045744:Cell Line, Tumor; D004965:Estrogen Antagonists / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D006801:Humans; D011485:Protein Binding; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D013629:Tamoxifen / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C111164:BRAP protein, human; D044767:Ubiquitin-Protein Ligases