GW4869 - N-SMase 抑制劑 - 生命科學試劑 - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEGW4869Cat. No.: HY-19363CAS No.: 6823-69-4分式: CHClNO分量: 577.5作靶點: Others作通路: Others儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實驗 H2O : 0.1 mg/mL (insoluble)DMSO : 0.044 mg/mL (0.08 mM; Need ultr

2、asonic and warming)請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。BIOLOGICAL ACTIVITY物活性 GW4869競爭性的中性鞘磷脂酶 (N-SMase)抑制劑 (外泌體抑制劑)，IC50值為1 M。IC50 & Target IC50: 1 M (neutral sphingomyelinase) 1體外研究GW4869 (10 M) partially inhibits TNF-induced sphingomyelin (SM) hydrolysis, and 20 M of the compoundis protec

3、ted completely from the loss of SM. The addition of 10-20 M GW4869 completely inhibits the initialaccumulation of ceramide, whereas this effect is partially lost at later time points (24 h). The action ofGW4869 occurs downstream of the drop in glutathione. GW4869 is able, in a dose-dependent manner,

4、 tosignificantly protect from cell death 1.GW4869 (10 or 20 M) inhibits both exosome release and pro-inflammatory cytokine production inmacrophages 2.GW4869 also could reverse the inhibition of CCN2 3-UTR activity by miR-214-enriched exosomes in hepaticstellate cells 3.Solution Attention: GW4869 is

5、routinely stored at 80C as a 1.5 mM stock suspension in DMSO (Me2SO).1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemERight before use, the suspension is solubilized by the addition of 5% methane sulfonic acid (MSA) (2.5 l of5% MSA in sterile double-distilled H2O are added to 50 L of GW4869 stock su

6、spension) 1. GW4869 isroutinely stored at -30 C as a 1.5 mM stock suspension in DMSO. Immediately before use, this suspensionis solubilized by the addition of 0.25% methane sulfonic acid (2.5 mL of 5% methane sulfonic acid in steriledistilled H2O is added to 47.5 mL of GW4869 stock solution). The su

7、spension is mixed and heated at 37 Cuntil clear 4.Cell Viability Assay 1Cell Line: MCF7 human breast cancer cells.Concentration: 10-20 M.Incubation Time: 30 min (then treated with TNF (3 nM) followed).Result: Significantly inhibited TNF-induced SM hydrolysis, whereas 20 M of the compoundprotected co

8、mpletely from the loss of SM.Cell Viability Assay 2Cell Line: Fresh RAW264.7 macrophages.Concentration: 10 or 20 M.Incubation Time: 2 hours (then treated with 1 g/mL LPS incubation).Result: LPS-triggered exosome generation was remarkably attenuated in macrophages uponpre-treatment of macrophages wit

9、h 10 M GW4869, as evidenced by a 22% reduction inthe activity of AChE. Such attenuation was further enhanced by treatment with the doseof 20 M.體內(nèi)研究GW4869 (2.5 g/g, i.p.) caused Inhibition of exosome release blocks LPS-stimulated pro-inflammatorycytokine production and cardiac inflammation in mice. G

10、W4869 mitigates LPS-caused myocardialdysfunction and improves survival in mice 2.GW4869 (2.5 g/g, i.p.) blocks the production of pro-inflammatory cytokines and cardiac inflammation in CLPmice 2.Animal Model: 10-12 weeks old Male wild-type C57BL/6 mice (Endotoxin-Challenged Mice) 2.Dosage: 2.5 g/g.Ad

11、ministration: I.P. once (1 h later, followed by an i.p. injection of LPS (25 g/g, 100L).Result: Significantly decreased exosome levels by 37% in sera, compared to levels collectedfrom control mice. At 12 h after LPS injection, the levels of circulating exosomeswereincreased significantly compared to

12、 PBS-controls, as evidenced by a 1.7-fold elevation inthe AChE activity.2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEAnimal Model: 10-12 weeks old Male wild-type C57BL/6 mice (CLP Polymicrobial Sepsis Model) 2.Dosage: 2.5 g/g.Administration: I.P. once (before sham or CLP surgery).Result: Decreas

13、ed exosome concentration by 33% compared to mice injected with PBS in sham-surgery controls.CLP-stimulated exosome release was significantly inhibited by pre-treatment of CLPmice compared to CLP mice pre-treated with PBS.戶使本產(chǎn)品發(fā)表的科研獻 J Exp Clin Cancer Res. 2019 Jul 15;38(1):310. Int J Oncol. 2019 May

14、;54(5):1567-1578.See more customer validations on HYPERLINK / www.MedChemEREFERENCES1. Luberto C, et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutralsphingomyelinase. J BiolChem. 2002 Oct 25;277(43):41128-39.2. Essandoh K, et al. Blockade of exosome

15、generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.Biochim Biophys Acta. 2015 Nov;1852(11):2362-71.3. Chen L, et al. Integrins and heparan sulfate proteoglycans on hepatic stellate cells (HSC) are novel receptors for HSC-derivedexosomes. FEBS Lett. 2016 Dec;590(23):4263-4274.4. Nakamura H, et al. Sphingomyelin Regulates the Activity of Secretory Phospholipase A2 in the Plasma Membrane. J Cell Bi