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

Area of Science:

• Pharmacology
• Oncology
• Medicinal Chemistry

Background:

• Estrogen receptors (ERα, ERβ, and GPER) mediate estrogen signaling, with GPER being a key target for ER-negative and triple-negative breast cancers.
• Existing GPER modulators have shown limited efficacy and contradictory results in cancer cell lines.
• Novel therapeutic strategies targeting GPER are needed for effective breast cancer treatment.

Purpose of the Study:

• To identify novel chemical scaffolds with specific antiproliferative effects against GPER-expressing breast cancer cell lines.
• To evaluate the efficacy of identified compounds in GPER-positive and GPER-negative cancer models.
• To elucidate the mechanism of action of promising GPER modulators.

Main Methods:

• Virtual screening was employed to identify potential GPER modulators.
• Cell-based assays were conducted to assess antiproliferative activity in various breast cancer cell lines.
• Western blotting was used to analyze the expression of cell cycle regulators (cyclin D1, p53, p21).

Main Results:

• Four novel chemical scaffolds with antiproliferative effects were identified.
• Compound 14c (8-chloro-4-(4-chlorophenyl)pyrrolo[1,2-a]quinoxaline) demonstrated significant antiproliferative activity in GPER-expressing cell lines (MCF7, SKBR3).
• Compound 14c showed no effect on GPER-negative cells (HEK293) and reduced cyclin D1 while increasing p53 and p21 expression.

Conclusions:

• Compound 14c is a potent and selective GPER modulator with significant antiproliferative activity against GPER-expressing breast cancer cells.
• The observed effects are mediated by the downregulation of cyclin D1 and upregulation of cell-cycle inhibitors p53 and p21.
• This study provides a promising new chemical scaffold for the development of targeted therapies for ER-negative and triple-negative breast cancer.