Abstract
The biologic effects of estrogens are transduced by two estrogen receptors (ERs), ERα and ERβ, which function in dimer forms. The ERα/α homodimer promotes and the ERβ/β inhibits estrogen-dependent growth of mammary epithelial cells; the functions of ERα/β heterodimers remain elusive. Using compounds that promote ERα/β heterodimerization, we have previously shown that ERα/β heterodimers appeared to inhibit tumor cell growth and migration in vitro. Further dissection of ERα/β heterodimer functions was hampered by the lack of ERα/β heterodimer-specific ligands. Herein, we report a multistep workflow to identify the selective ERα/β heterodimer-inducing compound. Phytoestrogenic compounds were first screened for ER transcriptional activity using reporter assays and ER dimerization preference using a bioluminescence resonance energy transfer assay. The top hits were subjected to in silico modeling to identify the pharmacophore that confers ERα/β heterodimer specificity. The pharmacophore encompassing seven features that are potentially important for the formation of the ERα/β heterodimer was retrieved and subsequently used for virtual screening of large chemical libraries. Four chemical compounds were identified that selectively induce ERα/β heterodimers over their respective homodimers. Such ligands will become unique tools to reveal the functional insights of ERα/β heterodimers.
Footnotes
- Received March 15, 2017.
- Accepted December 11, 2017.
↵1 C.G.C. and F.L. contributed equally to this work.
This work was supported by the National Institutes of Health National Cancer Institute [Grant R01 CA213293] to W.X.; the National Institutes of Health National Institute of Environmental Health Sciences [Grant T32ES007015] to C.G.C.; the University of Wisconsin Comprehensive Cancer Center Support [Grant P30CA014520] (for partial support of this work); and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant U54DK104310].
↵This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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