A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling.,Cell Chemical Biology

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A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling.
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2019-11-06 , DOI: 10.1016/j.chembiol.2019.10.009
Chetana M Revankar ₁ , Cristian G Bologa ₂ , Richard A Pepermans ₃ , Geetanjali Sharma ₃ , Whitney K Petrie ₁ , Sara N Alcon ₁ , Angela S Field ₁ , Chinnasamy Ramesh ₄ , Matthew A Parker ₅ , Nikolay P Savchuk ₅ , Larry A Sklar ₆ , Helen J Hathaway ₇ , Jeffrey B Arterburn ₈ , Tudor I Oprea ₉ , Eric R Prossnitz ₁₀

Affiliation

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.
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.
Department of Internal Medicine, Division of Molecular Medicine, 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.
Chemical Diversity Labs Inc., San Diego, CA 92121, USA.
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.
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.
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.
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.
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.

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.

中文翻译：

雌激素受体蛋白的选择性配体可区分快速信号和基因组信号。

雌激素在整个女性体内发挥着广泛而多样的作用。除了经典的核雌激素受体（ERα和ERβ）外，G蛋白偶联的雌激素受体GPER是雌激素作用的重要介体。现有的靶向ER的治疗剂可作为GPER激动剂。在这里，我们报告一个名为AB-1的小分子的鉴定，该分子具有与GPER结合的经典ER的高选择性活性，该活性先前未得到确认。AB-1还具有独特的功能活性谱，作为转录活性的激动剂，但却是通过ERα进行快速信号传递的拮抗剂。我们的结果定义了一类小分子，它们可以区分经典ER和GPER，以及经典ER中的信号传导模式。如果发展成ER拮抗剂，这种活性特征，

更新日期：2019-11-09

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