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GSK682753A Sale

目录号 : GC31651

GSK682753A是EB病毒诱导受体2(EBI2)的反向激动剂,IC50值为53.6nM。

GSK682753A Chemical Structure

Cas No.:1334294-76-6

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥1,204.00
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5mg
¥1,294.00
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10mg
¥2,186.00
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25mg
¥3,925.00
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50mg
¥7,020.00
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100mg
¥10,800.00
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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment:

The effect of GSK682753A on cAMP-induced CREB activation is measured. GSK682753A at varying concentrations is added when the transfection is stopped with a DMSO concentration after compound addition of 0.1%. The CREB activity is determined 24 h after transfection using the LucLite substrate[1].

References:

[1]. Benned-Jensen T, et al. Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist. J Biol Chem. 2011 Aug 19;286(33):29292-302.

产品描述

GSK682753A is a selective and highly potent inverse agonist of the epstein-barr virus-induced receptor 2 (EBI2) with an IC50 of 53.6 nM.

GSK682753 is a selective and highly potent inverse agonist for murine as well as human EBI2 with inhibition of G protein-dependent signals as well as signals that are probably G protein-independent. In cAMP-response element-binding protein-based reporter and guanosine5'-3-O-(thio)-triphosphate (GTPγS) binding assays, the potency of this compound is 2.6-53.6 nM, and its inhibitory efficacy is 75%. GSK682753A dose-dependently inhibits EBI2 with an IC50of 53.6 nM. GSK682753A inhibits ERK phosphorylation, GTPγS binding, and cAMP-response element-binding protein activation with similar potency[1].

[1]. Benned-Jensen T, et al. Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist. J Biol Chem. 2011 Aug 19;286(33):29292-302.

Chemical Properties

Cas No. 1334294-76-6 SDF
Canonical SMILES O=C1OC2(CCN(C(/C=C/C3=CC=C(Cl)C=C3)=O)CC2)CN1CC4=CC=C(Cl)C(Cl)=C4
分子式 C23H21Cl3N2O3 分子量 479.78
溶解度 DMSO : ≥ 27 mg/mL (56.28 mM) 储存条件 4°C, protect from light
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1 mM 2.0843 mL 10.4214 mL 20.8429 mL
5 mM 0.4169 mL 2.0843 mL 4.1686 mL
10 mM 0.2084 mL 1.0421 mL 2.0843 mL
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Research Update

Structures of oxysterol sensor EBI2/GPR183, a key regulator of the immune response

Oxysterols induce the migration of B-lymphocytes and dendritic cells to interfollicular regions of lymphoid tissues through binding the EBI2 (GPR183) to stimulate effective adaptive immunity and antibody production during infection. Aberrant EBI2 signaling is implicated in inflammatory bowel disease, sclerosis, and infectious disease. Here, we report the cryo-EM structures of an EBI2-Gi signaling complex with its endogenous agonist 7α,25-OHC and that of an inactive EBI2 bound to the inverse agonist GSK682753A. These structures reveal an agonist binding site for the oxysterol and a potential ligand entrance site exposed to the lipid bilayer. Mutations within the oxysterol binding site and the Gαi interface attenuate G protein signaling and abolish oxysterol-mediated cell migration indicating that G protein signaling directly involves in the oxysterol-EBI2 pathway. Together, these findings provide new insight into how EBI2 is activated by an oxysterol ligand and will facilitate the development of therapeutic approaches that target EBI2-linked diseases.

Small molecule antagonism of oxysterol-induced Epstein-Barr virus induced gene 2 (EBI2) activation

The Epstein-Barr virus induced gene 2 (EBI2) was recently identified as the first oxysterol-activated 7TM receptor. EBI2 is essential for B cell trafficking within lymphoid tissues and thus the humoral immune response in general. Here we characterize the antagonism of the non-peptide molecule GSK682753A, which blocks oxysterol-induced G-protein activation, β-arrestin recruitment and B-cell chemotaxis. We furthermore demonstrate that activation triggers pertussis toxin-sensitive MAP kinase phosphorylation, which is also inhibited by GSK682753A. Thus, EBI2 signalling in B cells mediates key phenotypic functions via signalling pathways amenable to manipulation providing additional therapeutic options for inhibiting EBI2 activity.

Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist

The Epstein-Barr virus-induced receptor 2 (EBI2) is a constitutively active seven-transmembrane receptor, which was recently shown to orchestrate the positioning of B cells in the follicle. To date, no ligands, endogenously or synthetic, have been identified that modulate EBI2 activity. Here we describe an inverse agonist, GSK682753A, which selectively inhibited the constitutive activity of EBI2 with high potency and efficacy. In cAMP-response element-binding protein-based reporter and guanosine 5'-3-O-(thio)triphosphate (GTPγS) binding assays, the potency of this compound was 2.6-53.6 nm, and its inhibitory efficacy was 75%. In addition, we show that EBI2 constitutively activated extracellular signal-regulated kinase (ERK) in a pertussis toxin-insensitive manner. Intriguingly, GSK682753A inhibited ERK phosphorylation, GTPγS binding, and cAMP-response element-binding protein activation with similar potency. Overexpression of EBI2 profoundly potentiated antibody-stimulated ex vivo proliferation of murine B cells compared with WT cells, whereas this was equivalently reduced for EBI2-deficient B cells. Inhibition of EBI2 constitutive activity suppressed the proliferation in all cases. Importantly, the suppression was of much higher potency (32-fold) in WT or EBI2-overexpressing B cells compared with EBI2-deficient counterparts. Finally, we screened GSK682753A against an EBI2 mutant library to determine putative molecular binding determinants in EBI2. We identified Phe(111) at position III:08/3.32 as being crucial for GSK682753A inverse agonism because Ala substitution resulted in a >500-fold decrease in IC(50). In conclusion, we present the first ligand targeting EBI2. In turn, this molecule provides a useful tool for further characterization of EBI2 as well as serving as a potent lead compound.