Identification of Breast Cancer Inhibitors Specific for GProtein-Coupled Estrogen Receptor (GPER)-Expressing Cells

Together with estrogen receptors ER[alpha] and ER[beta], the Gprotein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a fe...

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Bibliographic Details
Published in:ChemMedChem 2017-08, Vol.12 (16), p.1279
Main Authors: Aiello, Francesca, Carullo, Gabriele, Giordano, Francesca, Spina, Elena, Nigro, Alessandra, Garofalo, Antonio, Tassini, Sabrina, Costantino, Gabriele, Vincetti, Paolo, Bruno, Agostino, Radi, Marco
Format: Article
Language:English
Subjects:
Biotechnology
Breast cancer
Cancer
Estrogen receptors
Estrogens
GTP-binding protein
Modulators
p53 Protein
Quinoxaline
Receptors
Regulators
Scaffolds
Tumor cell lines
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Summary:Together with estrogen receptors ER[alpha] and ER[beta], the Gprotein-coupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens and is currently regarded as a promising target for ER-negative (ER-) and triple-negative (TN) breast cancer. Only a few selective GPER modulators have been reported to date, and their use in cancer cell lines has often led to contradictory results. Herein we report the application of virtual screening and cell-based studies for the identification of new chemical scaffolds with a specific antiproliferative effect against GPER-expressing breast cancer cell lines. Out of the four different scaffolds identified, 8-chloro-4-(4-chlorophenyl)pyrrolo[1,2-a]quinoxaline 14c was found to be the most promising compound able to induce: 1)antiproliferative activity in GPER-expressing cell lines (MCF7 and SKBR3), similarly to G15; 2)no effect on cells that do not express GPER (HEK293); 3)a decrease in cyclinD1 expression; and 4)a sustained induction of cell-cycle negative regulators p53 and p21.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700145