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

Estrogen exerts extensive and diverse effects throughout the body of women. In addition to the classical nuclear estrogen receptors (ER alpha and ER beta), 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 ER alpha. 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.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
breast-cancer
international-union
nongenomic actions
gene-expression
gper function
activation
gpr30
alpha
agonists
cells
Biochemistry & Molecular Biology

Bologa, C. G. (author)
Pepermans, R. A. (author)
Sharma, G. (author)
Petrie, W. K. (author)
Alcon, S. N. (author)
Field, A. S. (author)
Ramesh, C. (author)
Parker, M. A. (author)
Savchuk, N. P. (author)
Sklar, L. A. (author)
Hathaway, H. J. (author)
Arterburn, J. B. (author)
Oprea, Tudor IGothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research (author)
Prossnitz, E. R. (author)
Göteborgs universitetInstitutionen för medicin, avdelningen för reumatologi och inflammationsforskning (creator_code:org_t)

By the author/editor: Revankar, C. M.; Bologa, C. G.; Pepermans, R. A.; Sharma, G.; Petrie, W. K.; Alcon, S. N.; show more...; Field, A. S.; Ramesh, C.; Parker, M. A.; Savchuk, N. P.; Sklar, L. A.; Hathaway, H. J.; Arterburn, J. B.; Oprea, Tudor I; Prossnitz, E. R.; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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