Estrogen is a critical hormone in the human body that regulates the growth, development and homeostasis of many tissues. Physiological responses to estrogen include the regulation of mammalian reproduction and breast function, central nervous and immune systems, skeletal physiology and vascular function. We have recently described novel functions of the seven transmembrane G protein-coupled estrogen receptor, GPR30. This receptor is activated by both agonists and antagonists of the classical estrogen receptors, ER1 and ER2. Until recently there were no known specific ligands for GPR30, making traditional pharmacological approaches to the study of this receptor difficult. Our recent studies however have combined both virtual and biomolecular screening to discover the first GPR30-selective agonist, G-1.
The specific aims of this application are: 1. Perform a combination of virtual and biomolecular screening to identify additional GPR30-specific ligands based on compounds presently known to bind and activate GPR30. Structure-activity analyses will be carried out to determine the critical molecular determinants for GPR30 binding selectivity and activity as compared to classical estrogen receptors. 2. Based on the biomolecular screening results and structure-activity analyses of Aim 1, rationally design and synthesize small libraries (up to 20 compounds per cycle) of novel G-1-based ligands. The goal of this aim is to separate agonism from antagonism within ligands, and to further evaluate the SAR of novel GPR30 ligands through targeted synthetic chemistry. 3. Characterize the biological functions of the compounds identified and synthesized in Aims 1 and 2. A collection of functional bioassays will be employed to characterize the biological effects of the compounds displaying activity. These assays will include intracellular signaling assays such as calcium mobilization, ERK and EGFR phosphorylation and PI3K activation;more complex cellular assays such as transcriptional activation, cell migration and proliferation;and in vivo studies using mouse models. Understanding the pharmacological profile and structure-activity relationships for ligand binding to GPR30 will be critical to the discovery of novel drugs that target this receptor for the purposes of revealing the underlying physiology of the receptor and developing therapeutic approaches for the improved treatment of estrogen-dependent cancers.

Public Health Relevance

Estrogen plays an important role in normal and disease biology. We have characterized a novel membrane estrogen receptor that likely plays a role in estrogen biology. The goal of this work is to develop novel compounds that can specifically target this new receptor to either activate or inhibit its activity without affecting other estrogen receptors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Fu, Yali
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University of New Mexico
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Prossnitz, Eric R; Barton, Matthias (2014) Estrogen biology: new insights into GPER function and clinical opportunities. Mol Cell Endocrinol 389:71-83
Scaling, Allison L; Prossnitz, Eric R; Hathaway, Helen J (2014) GPER mediates estrogen-induced signaling and proliferation in human breast epithelial cells and normal and malignant breast. Horm Cancer 5:146-60
Vaucher, Laurent; Funaro, Michael G; Mehta, Akanksha et al. (2014) Activation of GPER-1 estradiol receptor downregulates production of testosterone in isolated rat Leydig cells and adult human testis. PLoS One 9:e92425
Nayak, Tapan K; Ramesh, Chinnasamy; Hathaway, Helen J et al. (2014) GPER-targeted, 99mTc-labeled, nonsteroidal ligands demonstrate selective tumor imaging and in vivo estrogen binding. Mol Cancer Res 12:1635-43
Barton, Matthias; Meyer, Matthias R; Prossnitz, Eric R (2013) Alike but not the same: anatomic heterogeneity of estrogen receptor-mediated vasodilation. J Cardiovasc Pharmacol 62:22-5
Brunsing, Ryan L; Owens, Kristin S; Prossnitz, Eric R (2013) The G protein-coupled estrogen receptor (GPER) agonist G-1 expands the regulatory T-cell population under TH17-polarizing conditions. J Immunother 36:190-6
Sharma, Geetanjali; Hu, Chelin; Brigman, Jonathan L et al. (2013) GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state. Endocrinology 154:4136-45
Meyer, Matthias R; Field, Angela S; Kanagy, Nancy L et al. (2012) GPER regulates endothelin-dependent vascular tone and intracellular calcium. Life Sci 91:623-7
Meyer, Matthias R; Amann, Kerstin; Field, Angela S et al. (2012) Deletion of G protein-coupled estrogen receptor increases endothelial vasoconstriction. Hypertension 59:507-12
Dennis, Megan K; Field, Angela S; Burai, Ritwik et al. (2011) Identification of a GPER/GPR30 antagonist with improved estrogen receptor counterselectivity. J Steroid Biochem Mol Biol 127:358-66

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