An inhibitor of NF-κB/AP-1
IQ-1S (free acid) is an inhibitor of NF-κB/AP-1 (IC50 = 2.3 ?M in a reporter assay).1 It inhibits TNF-α and IL-6 production in human Mono-Mac-6 cells (IC50s = 1.3 and 3.8 ?M, respectively) and isolated human peripheral blood mononuclear cells (PBMCs; IC50s = 2.6 and 5.6 ?M, respectively), as well as nitric oxide (NO) production in murine J774-A.1 macrophages (IC50 = 3.1 ?M). IQ-1S (free acid) binds to JNKs (Kd = 0.24, 0.36, and 0.1?M for JNK1-3), as well as casein kinase 1δ (CK1δ), PI3Kγ, and MAPK-interacting serine/threonine kinase 2 (MKNK2; Kds = 0.38, 0.47, and 0.92 ?M, respectively).
1.Schepetkin, I.A., Kirpotina, L.N., Khlebnikov, A.I., et al.Identification and characterization of a novel class of c-Jun N-terminal kinase inhibitorsMol. Pharmacol.81(6)832-845(2012)
Cell experiment: | Human PBMCs are plated in 96-well plates at a density of 2×105 cells/well in culture medium supplemented with 3% (v/v) endotoxin-free FBS. PBMCs are pretreated with 20 μM IQ-1S or DMSO for 30 min, followed by addition of 200 ng/ml LPS for 24 h. A human cytokine MultiAnalyte ELISArray Kit is used to evaluate various cytokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17A, interferon (IFN)-γ, TNF-α, and granulocyte-macrophage colony-stimulating factor in supernatants of PBMCs[1]. |
Animal experiment: | Mice[1]For in vivo analysis, 12.5 or 30 mg/kg i.p. doses of IQ-1S (The sodium salt of IQ-1) are administered to BALB/c mice (15-20 animals/group), and the mice are sacrificed at various time points after compound administration. For quantification, a calibration curve is established using mouse serum samples spiked with known concentrations of IQ-1S (0.1-20 μM), and a linear dependence of the peak area with IQ-1S concentration is obtained (correlation coefficient r=0.997). The area under the serum concentration-time curve (AUC0-12h) is calculated using the linear trapezoidal method up to the last measured concentration[1]. |
参考文献: [1]. Schepetkin IA, et al. Identification and characterization of a novel class of c-Jun N-terminal kinase inhibitors. Mol Pharmacol. 2012 Jun;81(6):832-45. | |
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