期刊
CELL CHEMICAL BIOLOGY
卷 26, 期 12, 页码 1692-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2019.10.009
关键词
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资金
- NIH [CA127731, CA163890, CA194496]
- Cowboys for Cancer Research Foundation
- Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism [P20 GM121176]
- University of New Mexico Comprehensive Cancer Center [P30 CA118100]
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.
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