A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling

Chetana M Revankar; Cristian G Bologa; Richard A Pepermans; Geetanjali Sharma; Whitney K Petrie; Sara N Alcon; Angela S Field; Chinnasamy Ramesh; Matthew A Parker; Nikolay P Savchuk; Larry A Sklar; Helen J Hathaway; Jeffrey B Arterburn; Tudor I Oprea; Eric R Prossnitz

doi:10.1016/j.chembiol.2019.10.009

A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling

Cell Chem Biol. 2019 Dec 19;26(12):1692-1702.e5. doi: 10.1016/j.chembiol.2019.10.009. Epub 2019 Nov 6.

Authors

Affiliations

¹ Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
² Department of Internal Medicine, Division of Translational Informatics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
³ Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
⁴ Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA.
⁵ Chemical Diversity Labs Inc., San Diego, CA 92121, USA.
⁶ Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
⁷ Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
⁸ University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA.
⁹ Department of Internal Medicine, Division of Translational Informatics, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹⁰ Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. Electronic address: eprossnitz@salud.unm.edu.

Abstract

Estrogen exerts extensive and diverse effects throughout the body of women. In addition to the classical nuclear estrogen receptors (ERα and ERβ), the G protein-coupled estrogen receptor GPER is an important mediator of estrogen action. Existing ER-targeted therapeutic agents act as GPER agonists. Here, we report the identification of a small molecule, named AB-1, with the previously unidentified activity of high selectivity for binding classical ERs over GPER. AB-1 also possesses a unique functional activity profile as an agonist of transcriptional activity but an antagonist of rapid signaling through ERα. Our results define a class of small molecules that discriminate between the classical ERs and GPER, as well as between modes of signaling within the classical ERs. Such an activity profile, if developed into an ER antagonist, could represent an opportunity for the development of first-in-class nuclear hormone receptor-targeted therapeutics for breast cancer exhibiting reduced acquired and de novo resistance.

Keywords: ERα; ERβ; GPER; GPR30; SERD; SERM; breast cancer; estrogen; receptors.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Proliferation / drug effects
Estradiol / pharmacology
Estrogen Receptor alpha / antagonists & inhibitors
Estrogen Receptor alpha / metabolism*
Estrogen Receptor beta / antagonists & inhibitors
Estrogen Receptor beta / metabolism*
Female
Forkhead Box Protein O3 / genetics
Forkhead Box Protein O3 / metabolism
Humans
Ligands*
MCF-7 Cells
Mice
Mice, Inbred C57BL
Protein Binding
Receptors, Estrogen / genetics
Receptors, Estrogen / metabolism
Receptors, G-Protein-Coupled / agonists
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Signal Transduction* / drug effects
Transcription, Genetic / drug effects
Uterus / drug effects
Uterus / metabolism

Substances

Estrogen Receptor alpha
Estrogen Receptor beta
FOXO3 protein, human
Forkhead Box Protein O3
GPER1 protein, human
Ligands
Receptors, Estrogen
Receptors, G-Protein-Coupled
Estradiol

Abstract

Publication types

MeSH terms

Substances

Grants and funding