Small-Molecule 'BRCA1-Mimetics' Are Antagonists of Estrogen Receptor-α
| Autor: | Eliseu O. De Oliveira, Anju Preet, Eliot M. Rosen, Scott Grindrod, Shyam Nathan, Milton L. Brown, Erikah Englund, Robert Clarke, York Tomita, Yongxian Ma |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Selective Estrogen Receptor Modulators
medicine.drug_class Ubiquitin-Protein Ligases Estrogen receptor Pharmacology Biology Endocrinology Estrogen Receptor Modulators Cell Line Tumor Coactivator medicine Humans Molecular Biology Estrogen receptor beta Original Research Estrogen Antagonists Estrogen Receptor alpha General Medicine Surface Plasmon Resonance Tamoxifen Estrogen Selective estrogen receptor modulator Pharmacophore Estrogen receptor alpha medicine.drug Protein Binding |
| Popis: | Context: 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. Design: 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). |
| Databáze: | OpenAIRE |
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