A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling. Issue 12 (19th December 2019)

• Record Type: Journal Article
• Authors: Revankar, Chetana M.; Bologa, Cristian G.; Pepermans, Richard A.; Sharma, Geetanjali; Petrie, Whitney K.; Alcon, Sara N.; Field, Angela S.; Ramesh, Chinnasamy; Parker, Matthew A.; Savchuk, Nikolay P.; Sklar, Larry A.; Hathaway, Helen J.; Arterburn, Jeffrey B.; Oprea, Tudor I.; Prossnitz, Eric R.
• Is Part Of: Cell chemical biology. Volume 26:Issue 12(2019)
• Page Start: 1692
• Page End: 1702.e5
• Publication Date: 2019-12-19
• Subjects: breast cancer -- estrogen -- ERα -- ERβ -- GPER -- GPR30 -- receptors -- SERM -- SERD; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2019.10.009
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Identification of the first ER-selective ligand (AB-1) that lacks GPER cross-reactivity AB-1 binds with high affinity to ERα and ERβ, but not to GPER GPER-mediated signaling pathways are not activated by AB-1 AB-1 initiates ER-mediated transcription but not rapid signaling by ER Abstract : ER-selective ligands lacking GPER cross-reactivity remain unknown. Revankar et al. identify an ER-targeted ligand, termed AB-1, with high selectivity for ER over GPER. AB-1 activates ER transcription while antagonizing ER rapid signaling. This activity profile, if converted into an antagonist, could prove beneficial in breast cancer treatment.