Background: Recent reports have demonstrated the role of the G Protein-Coupled Estrogen Receptor
1 (GPER1) on the proliferation of breast cancer. The coupling of GPER1 to estrogen triggers cellular signaling
pathways related to cell proliferation.
Objective: Develop new therapeutic strategies against breast cancer.
Method: We performed in silico studies to explore the binding mechanism of a set of G15 /G1 analogue compounds.
We included a carboxyl group instead of the acetyl group from G1 to form amides with several moieties
to increase affinity on GPER1. The designed ligands were submitted to ligand-based and structure-based virtual
screening to get insights into the binding mechanism of the best designed compound and phenol red on GPER1.
Results: According to the in silico studies, the best molecule was named G1-PABA ((3aS,4R,9bR)-4-(6-
bromobenzo[d][1,3]dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-carboxylic acid). It was
synthesized and assayed in vitro in breast cancer (MCF-7 and MDA-MB-231) and normal (MCF-10A) cell
lines. Experimental studies showed that the target compound was able to decrease cell proliferation, IC50 values
of 15.93 µM, 52.92 µM and 32.45 µM in the MCF-7, MDA-MB-231 and MCF-10A cell lines, respectively,
after 72 h of treatment. The compound showed better IC50 values without phenol red, suggesting that phenol red
interfere with the G1-PABA action at GPER1, as observed through in silico studies, which is present in MCF-7
cells according to PCR studies and explains the cell proliferation effects.
Conclusion: Concentration-dependent inhibition of cell proliferation occurred with G1-PABA in the assayed
cell lines and could be due to its action on GPER1.