Resistance to conventional anti-estrogens is a major cause of treatment failure and, ultimately, death in breast cancer.
Ma Y, Tomita Y, Preet A, et al. Small Molecule “BRCA1-Mimetics” are Antagonists of Estrogen Receptor-alpha. Molecular Endocrinology. http://press.endocrine.org/doi/abs/10.1210/me.2014-1146
Objective. To identify small molecule estrogen receptor (ER-α) antagonists that work differently from Tamoxifen and other selective estrogen receptor modulators (SERMs).
Design. Based on in silico screening of a pharmacophore database utilizing 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 3–50 μ M. These ER-α inhibitory compounds were further studied by molecular and cell biologic techniques.
Results. The compounds strongly inhibited ER-α activity at concentrations that yielded little or no non-specific toxicity, but they produced only modest inhibition of progesterone receptor activity. Importantly, the compounds blocked proliferation and inhibited ER-α activity about equally well in anti-estrogen-sensitive and anti-estrogen resistant breast cancer cells. Representative compounds disrupted the interaction of BRCA1 and ER-α in cultured cells and blocked the interaction of ER-α with the estrogen response element (ERE). 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 anti-estrogens (eg., Tamoxifen and Fulvestrant).
Ma Y, Tomita Y, Preet A, et al. Small Molecule “BRCA1-Mimetics” are Antagonists of Estrogen Receptor-alpha. Molecular Endocrinology. http://press.endocrine.org/doi/abs/10.1210/me.2014-1146
Objective. To identify small molecule estrogen receptor (ER-α) antagonists that work differently from Tamoxifen and other selective estrogen receptor modulators (SERMs).
Design. Based on in silico screening of a pharmacophore database utilizing 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 3–50 μ M. These ER-α inhibitory compounds were further studied by molecular and cell biologic techniques.
Results. The compounds strongly inhibited ER-α activity at concentrations that yielded little or no non-specific toxicity, but they produced only modest inhibition of progesterone receptor activity. Importantly, the compounds blocked proliferation and inhibited ER-α activity about equally well in anti-estrogen-sensitive and anti-estrogen resistant breast cancer cells. Representative compounds disrupted the interaction of BRCA1 and ER-α in cultured cells and blocked the interaction of ER-α with the estrogen response element (ERE). 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 anti-estrogens (eg., Tamoxifen and Fulvestrant).
