c-Jun N-terminal kinase (JNK) is a serine threonine protein kinase that belongs to the mitogen-activated protein kinase family. SP-600125 is an anthrapyrazolone inhibitor of JNK with IC50 values of 40, 40, and 90nM for JNK1, JNK2, and JNK3, respectively. SP-600125 also exhibits inhibitory activity against p56Lck, MMK3, MMK4, MMK6, MM7, PKB/AKT, and PKCα with IC50 values of 4.3, 1.5, 0.4, 1.0, 5.1, 1.0, and 1.5μM, respectively. SP-600125 inhibited JNK2 in an ATP-competitive manner with a Ki value of 0.19±0.06μM. It inhibited the phosphorylation of c-Jun in Jurkat T cells with an IC50 value of 5-10μM. In cells stimulated with PMA and phytohemagglutinin, SP-600125 inhibited both IL-2 and IFN-γ expression in a dose-dependent manner with IC50 values of 6 and 7μM, respectively. The incubation of Th1 cells with SP-600125 for 5 days potently inhibited the expression of IFN-γ, TNF-α, and IL-10 (IC50 = 7-12μM), but only weakly blocked the production of IL-1β and IL-6 (IC50 > 30μM). In primary human peripheral blood mononuclear cells stimulated with LPS (100 ng/ml) for 4 h, treatment with SP-600125 dose-dependently inhibited the mRNA expression of COX-2 and TNF-α with IC50 values of 5 and 10μM. In CD-1 mice induced with LPS, intravenous administration of SP-600125 significantly decreased the serum level of TNF-α at doses of 15 and 30mg/kg, while oral administration of 30mg/kg SP-600125 significantly inhibited TNF-α expression compared to the vehicle-treated group[2].
作用机制
SP-600125 is a small-molecule, ATP-competitive inhibitor of JNK[1].
SP600125 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U87Δ cells
10 μM
24 hours
Inhibition of JNK activity significantly reduced IL-8 secretion
Oncogene. 2012 Sep 6;31(36):4054-66.
Human Cardiac Fibroblasts (HCFs)
3 μM
1-hour pretreatment followed by 12-hour TNF-α stimulation
Inhibition of TNF-α-induced CCL20 protein secretion, demonstrating the role of p38 MAPK in CCL20 expression
Induced luciferase signal through MISR2 activation, validating SP600125 as an MISR2 agonist
Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2122512119.
Primary murine microglia
10 μM
2, 8, 24 h
To study the effect of SP600125 on LPA-induced phosphorylation of STAT1, STAT3, p65, and c-Jun transcription factors, results showed that SP600125 inhibited the phosphorylation of STAT1 and STAT3.
J Neuroinflammation. 2020 Apr 23;17(1):127.
Primary murine microglia
10 μM
12, 24 h
To study the effect of SP600125 on LPA-induced expression of CD40, CD86, and CD206 membrane markers, results showed that SP600125 significantly downregulated CD40 expression.
J Neuroinflammation. 2020 Apr 23;17(1):127.
Primary murine microglia
10 μM
2, 8, 24 h
To study the effect of SP600125 on LPA-induced secretion of IL-6, TNFα, IL-1β, CXCL10, CXCL2, and CCL5, results showed that SP600125 significantly inhibited the secretion of these cytokines.
J Neuroinflammation. 2020 Apr 23;17(1):127.
Primary murine microglia
10 μM
0.5, 24 h
To study the effect of SP600125 on LPA-induced ROS and NO production, results showed that SP600125 significantly inhibited ROS and NO production.
Validated SP600125's ability to inhibit folliculogenesis in vivo, showing significant reduction in primary follicles but weaker effects on secondary and antral follicles
Proc Natl Acad Sci U S A. 2022 Apr 12;119(15):e2122512119.
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