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

Abstract

To gether with estrogen receptors ERa and ERb,t he Gproteincoupled estrogen receptor (GPER) mediates important pathophysiological signaling pathways induced by estrogens andi s currently regardeda sapromising target for ER-negative (ERÀ) and triple-negative( TN) breast cancer.O nly af ew 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 virtuals creening and cell-based studies for the identification of new chemical scaffoldsw ith as pecific 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 14 c was found to be the most promising compound able to induce:1 )antiproliferativea ctivity in GPER-expressing cell lines (MCF7 and SKBR3), similarly to G15;2 )noe ffect on cells that do not expressG PER (HEK293);3 )a decrease in cyclin D1 expression;a nd 4) as ustained induction of cell-cycle negative regulators p53 and p21.Breast cancer is the most common cancer diagnosis in women and the mostc ommon cause of cancer-related mortality among females worldwide, with current predictions and statistics suggesting that both incidence and mortality rates are on the rise. [1] Hormone receptor (HR) positive breast cancer( HR +) is the most common form of breast cancer( 85 %o fa ll breast cancers)a nd has ag ood prognosis thanks to endocrine therapy (e.g.,t amoxifen) and administration of aromatase inhibitors (e.g.,l etrozole). HRÀ human epidermal growth factor receptor 2p ositive (HER2 +), andt riple-negative (TN) breastc ancers (HER2À,E R aÀ,E R bÀ)h ave al ower incidence, but whereas HER2 + tumors can be treated with targeted therapies (e.g., trastuzumab),T Nt umorsh ave the worst prognosis, ag reater chance of recurrence, andnot argeted treatments. [2] Estrogen hormones playakey role not only in the regulation of multiple physiological processes, but also in promoting the proliferation of the neoplastic breast epithelium by acting on soluble nuclear estrogen receptors (ERa and ERb). [3] While tamoxifeni sawidely used selectivee strogen receptorm odulator (SERM) and displays anti-estrogenic (and therefore anticancer) effects in the breast, it also has pro-estrogenic activity in the endometrium, enhancing the risk of developing endometrial cancer. However,t he therapeutic benefito ft amoxifen in the treatment of breast cancer has been considered to outweigh the risk of developinge ndometrial canceri np remenopausal women. [4] These side effects seem to be due to the active metabolite of tamoxifen (4-hydroxytamoxifen, 4-OHT), which acts as an agonistf or at hird estrogenr eceptor involved in the rapid non-genomic response to estrogens:t he Gprotein-coupled estrogen receptor (GPER or GPR30). [5] GPER is now emerging as an ew potentialt arget for the treatment of severalh uman diseases such as cardiovascular,r enal, and proteinuria diseases and malignancy. [6] In the field of anticancer drug disco...

Computational Approaches for the Discovery of GPER Targeting Compounds

“…Similarly to G-15, theoretical methods have also been used to identify new compounds ( 61 ) with a selective anti-proliferative activity against GPER-expressing breast cancer cells. A virtual screening campaign was carried out on a chemical library of about 1,000 compounds, in search of molecules showing a binding mode close to G-15 and G-36.…”

Sequential ligand- and structure-based virtual screening approach for the identification of potential G protein-coupled estrogen receptor-1 (GPER-1) modulators

“…This type of hydrogen bonding is also previously reported. 42,52 Besides, hydrogen bonding network was formed by amino acid Glu218 with NH group of G1. Moreover, the amino acid residue of Asp210 contributed in hydrogen bond network to one of the oxygens in dioxole moiety, while Glu218 and Gln138 were involved in forming pi-anion and pi-donor hydrogen bond respectively with the aromatic ring of benzodioxole moiety of G1.…”

G-Protein Coupled Estrogen Receptor in Breast Cancer

“…The G-protein coupled estrogen receptor (GPER), originally known as GPR30, a seven transmembrane domain protein, is an alternate estrogen receptor with a structure distinct from the two canonical estrogen receptors, ERα and ERβ mainly mediate a rapid non-genomic response [5,6,7,8,9,10]. This is expressed in about 50% to 60% of breast cancer tissues and has been reported as a modulator of neoplastic transformation (Figure 2) [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. Paradoxically, the modulators or antagonists of the classical estrogen receptors such as tamoxifen, raloxifene, and fulvestrant, were found to be the GPER agonists [24].…”