Small-Molecule "BRCA1-Mimetics" Are Antagonists of Estrogen Receptor-α

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)-alpha 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-alpha complex (with ER-alpha liganded to 17 beta-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-alpha. Among 40 candidate compounds, six inhibited estradiol-stimulated ER-alpha activity by at least 50% in breast carcinoma cells, with IC50 values ranging between 3 and 50 mu M. These ER-alpha inhibitory compounds were further studied by molecular and cell biological techniques. Results: The compounds strongly inhibited ER-alpha 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-alpha activity about equally well in antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Representative compounds disrupted the interaction of BRCA1 and ER-alpha in the cultured cells and blocked the interaction of ER-alpha with the estrogen response element. However, the compounds had no effect on the total cellular ER-alpha levels. Conclusions: These findings suggest that we have identified a new class of ER-alpha antagonists that work differently from conventional antiestrogens (eg, tamoxifen and fulvestrant).