化合物GSK583 T3537

Product Introduction
Bioactivity


英文名: GSK583

描述: GSK583 是一种高效且特异性的 RIP2 激酶抑制剂，IC50值为 5 nM。它抑制 TNF-α 和 IL-6 的产生，IC50值为 200 nM。

细胞实验: To assess cellular selectivity, monocytes are pretreated with inhibitor for 30 min, then stimulated for 6 h with ligands which selectively agonize NLRs NOD1, NOD2; Toll-like receptors TLR, TLR4, TLR7, or cytokine receptors IL-1R, TNFR. Release of pro-inflammatory cytokines, either TNFα (NOD2, TLR2, TLR4, IL1R) or IL-8 (NOD1, TLR7, TNFR), is measured by immunoassay. Percent inhibition and/or IC50 values are calculated. (Only for Reference)

激酶实验: A fluorescent polarization based binding assay is developed to quantitate interaction of novel test compounds at the ATP binding pocket of RIP2K by competition with a fluorescently labeled ATP competitive ligand. Full length FLAG His tagged RIP2K is purified from a baculovirus expression system and is used at a final assay concentration of twice the KD apparent. A fluorescent labeled ligand that is reversible and competitive with the inhibitors is used at a final assay concentration of 5 nM. Both the enzyme and ligand are prepared in solutions in 50 mM HEPES pH 7.5, 150 mM NaCl, 10 mM MgCl2, 1 mM DTT, and 1 mM CHAPS. Test compounds are prepared in 100% DMSO, and 100 nL is dispensed to individual wells of a multiwell plate. Next, 5 μL of RIP2K is added to the test compounds at twice the final assay concentration and incubated at room temperature for 10 min. Following the incubation, 5 μL of the fluorescent labeled ligand solution is added to each reaction at twice the final assay concentration and incubated at room temperature for at least 10 min. Finally, samples are read on an instrument capable of measuring fluorescent polarization. Test compound inhibition is expressed as percent (%) inhibition of internal assay controls. For concentration response experiments, normalized data are fit using the following four parameter logistic equation: y = A + ((B-C))/(1+(10x)/(10C)D), where y is the % activity (% inhibition) at a specified compound concentration, A is the minimum % activity, B is the maximum % activity, C = log10(IC50), D = Hill slope, x = log10(compound concentration [M]), and pIC50 = (?C).

体外活性: GSK583 possesses a comparable binding affinity for RIP3 kinase similarly to the RIP2 (RIP2/3 FP IC50: 5/16 nM) by an in-house FP binding assay configured. But GSK583 (10 μM) shows little or no inhibition of RIP3-dependent necroptotic cell death in a cellular assay. GSK583 effectively and dose-dependently inhibits MDP-stimulated TNFα production (IC50: 8 nM) in primary human monocytes. Following treatment with GSK583 at 1 μM, little inhibition of pro-inflammatory signaling is observed upon activation of cytokine receptors (IL-1R, TNFR) or Toll-like receptors (TLR2, TLR4, TLR7) but complete inhibition is observed upon activation of NOD1/2 receptors, which signal in a RIP2-dependent manner. Although it has excellent kinase selectivity, GSK583 does inhibit both the hERG channel and CYP3A4.

体内活性: GSK583 has moderate volumes of distribution, low clearance, and moderate oral bioavailability (in rat and mouse). Although GSK583 would not produce a human pharmacodynamic response within an acceptable dose range, the oral PK in mouse and rat supplies enough systemic exposure for use as a preclinical in vivo tool molecule in an acute inflammation challenge model.

存储条件: Powder: -20°C for 3 years | In solvent: -80°C for 1 year

溶解度: DMSO : 73 mg/mL (183.2 mM)
H2O : < 1 mg/mL (insoluble or slightly soluble)
Ethanol : 27 mg/mL (67.8 mM)


关键字: RIPK | Inhibitor | Receptor-interacting protein kinases | RIP kinase | GSK-583 | GSK 583 | inhibit | GSK583

相关产品: GSK872 HCl（1346546-69-7 free base） | SZM-1209 | GSK2982772 | RIP2 Kinase Inhibitor 3 | RI-962 | Necrostatin-5 | RIP1 kinase inhibitor 6 | RIPK3-IN-4 | Zharp2-1 | Tuxobertinib

相关库: Anti-Aging Compound Library | HIF-1 Signaling Pathway Compound Library | Anti-Liver Cancer Compound Library | Pyroptosis Compound Library | Anti-Cancer Compound Library | Cytokine Inhibitor Library | NF-κB Signaling Compound Library | Inhibitor Library | Kinase Inhibitor Library | NO PAINS Compound Library

化合物GSK583 T3537信息由TargetMol中国为您提供，如您想了解更多关于化合物GSK583 T3537报价、型号、参数等信息，欢迎来电或留言咨询。

注：该产品未在中华人民共和国食品药品监督管理部门申请医疗器械注册和备案，不可用于临床诊断或治疗等相关用途