Identification of two benzopyrroloxazines acting as selective GPER antagonists in breast cancer cells and cancer-associated fibroblasts

Background: G-protein coupled estrogen receptor (GPER) is involved in numerousintracellular physiological and pathological events including cancer cell migrationand proliferation. Its characterization is yet incomplete due to the limited number ofspecific ligands. Results: Two novel selective GPER antagonists, based on a benzo[b]pyrrolo[1,2-d][1,4]oxazin-4-one structure, have been designed and synthesized. Theirbinding to the receptor was confirmed by a competition assay, while the antagonisteffects were ascertained by their capability to prevent the ligand-stimulated actionof GPER. The transcription mediated by the classical estrogen receptor was notinfluenced, demonstrating selectivity for GPER. Conclusion: These novel compoundsmay be considered useful leads toward the dissection of the GPER signaling and thedevelopment of new pharmacological treatments in breast cancer.