A Series of Indole-Thiazole Derivatives Act as GPER Agonists and Inhibit Breast Cancer Cell Growth

O'Dea, Austin T; Sondergard, Chelsea; Sweeney, Patrick J.; Arnatt, Christopher K.

doi:10.1021/acsmedchemlett.8b00212

Cited by 22 publications

(24 citation statements)

References 39 publications

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“…These compounds were shown to bind exclusively to GPER1 without significant ESR1 binding above 100 mM ( Figure 2) (33). Previously, we identified a series of N-thiazol-2-yl-1H-indole-2-carboxamide derivatives as GPER1 agonists (30). These compounds exhibited a similar effect on breast cancer proliferation as reported in the literature in response to the GPER1-selective agonist, G-1 ( Figure 2 and demonstrated that MIBE blocks agonist activity at both GPER1 and ESR1 (36,37).…”

Section: Current Ligands For the Modulation Of Gper1 Signalingsupporting

confidence: 56%

“…The reduction of binding and ERE activation was accomplished with the addition of an isopropyl group to the scaffold to make G-36 (29). While the G-series has become the standard for GPER1 agonists and antagonists, the success with the compounds has been variable and may be related to the tissue-specific signaling events of GPER1 (30,31).…”

Section: Current Ligands For the Modulation Of Gper1 Signalingmentioning

confidence: 99%

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G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases

2020

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Section: Current Ligands For the Modulation Of Gper1 Signalingsupporting

confidence: 56%

Section: Current Ligands For the Modulation Of Gper1 Signalingmentioning

confidence: 99%

G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases

2020

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“…On the basis of affinity or efficacy as transcriptional activators, some ligands have been revealed to discriminate between GPR30 and ER subtypes. (14)(15)(16)(17) Subsequently, a considerable effort has been focused on the development of receptor-selective agonists and antagonists for GPR30, ERα, or ERβ. A compound, G-1, has been found to be a cell-permeable, nonsteroidal, dihydroquinoline, high-affinity, selective agonist for GPR30, and it displays no activity on ERα or ERβ at concentrations up to 10 μM.…”

mentioning

confidence: 99%

Activation of Estrogen Receptor G Protein–Coupled Receptor 30 Enhances Cholesterol Cholelithogenesis in Female Mice

et al. 2020

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BaCKgRoUND aND aIMS: Estrogen is an important risk factor for cholesterol gallstone disease because women are twice as likely as men to form gallstones. The classical estrogen receptor α (ERα), but not ERβ, in the liver plays a critical role in the formation of estrogen-induced gallstones in female mice. The molecular mechanisms underlying the lithogenic effect of estrogen on gallstone formation have become more complicated with the identification of G protein-coupled receptor 30 (GPR30), an estrogen receptor. appRoaCH aND ReSUltS: We investigated the biliary and gallstone phenotypes in ovariectomized female GPR30 −/− , ERα −/− , and wild-type mice injected intramuscularly with the potent GPR30-selective agonist G-1 at 0 or 1 μg/day and fed a lithogenic diet for 8 weeks. The activation of GPR30 by G-1 enhanced cholelithogenesis by suppressing expression of cholesterol 7α-hydroxylase, the rate-limiting enzyme for the classical pathway of bile salt synthesis. These metabolic abnormalities led to an increase in biliary cholesterol concentrations in company with hepatic hyposecretion of biliary bile salts, thereby inducing cholesterol-supersaturated gallbladder bile and accelerating cholesterol crystallization. G-1 also impairs gallbladder emptying, leading to sluggish gallbladder motility and promoting the development of biliary sludge in the early stage of gallstone formation. The prevalence rates of gallstones were 80% in wild-type and ERα −/− mice treated with G-1 compared to 10% in wild-type mice receiving no G-1. However, no gallstones were formed in GPR30 −/− mice treated with G-1. CoNClUSIoNS: GPR30 produces additional lithogenic actions, working independently of ERα, to increase susceptible to gallstone formation in female mice; both GPR30 and ERα are potential therapeutic targets for cholesterol gallstone disease, particularly in women and patients exposed to high levels of estrogen. (Hepatology 2020;72:2077-2089). E pidemiological investigations and clinical studies have clearly demonstrated that estrogen is a critical risk factor for cholesterol cholelithiasis because gallstones are more common in women than in men at all ages in every population studied. (1) The biological effects of estrogen are ascribed to transcriptional modulation of target genes through two classical estrogen receptors (ERs), subtypes α and β (ERα and ERβ). Using quantitative real-time PCR techniques, hepatic expression of the Erα gene is found to be ∼50-fold higher compared with that of Erβ, suggesting that ERα is a major steroid hormone receptor for exerting the biological effects of estrogen in the liver. (2) To study the molecular mechanisms of how estrogen influences gallstone formation, we

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“…Previously, our group explored binding interactions in a series of indole-thiazole derivatives that exhibited agonism at GPER (42). Molecular homology modeling found that the indole-thiazole derivatives exhibited -stacking similar to G-1 of the aromatic groups with F206 45.49 and F208 45.51 within the binding pocket of GPER (33,34,42). These results suggested that the tetrahydroquinoline is not required for GPER activity.…”

Section: Discussionmentioning

confidence: 99%

A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice

DeLeon

Wang

Gunn

et al. 2020

Journal of Lipid Research

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Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (−/−) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.

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A Series of Indole-Thiazole Derivatives Act as GPER Agonists and Inhibit Breast Cancer Cell Growth

Cited by 22 publications

References 39 publications

G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases

G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases

Activation of Estrogen Receptor G Protein–Coupled Receptor 30 Enhances Cholesterol Cholelithogenesis in Female Mice

A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice

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