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

Autor:	Revankar CM; 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., Bologa CG; 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., Pepermans RA; Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Sharma G; Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Petrie WK; 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., Alcon SN; 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., Field AS; 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., Ramesh C; Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003, USA., Parker MA; Chemical Diversity Labs Inc., San Diego, CA 92121, USA., Savchuk NP; Chemical Diversity Labs Inc., San Diego, CA 92121, USA., Sklar LA; 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., Hathaway HJ; 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., Arterburn JB; 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., Oprea TI; 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., Prossnitz ER; 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.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2019 Dec 19; Vol. 26 (12), pp. 1692-1702.e5. Date of Electronic Publication: 2019 Nov 06.
DOI:	10.1016/j.chembiol.2019.10.009
Abstrakt:	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. (Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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