c-Jun N-terminal kinases (JNK1/2/3) are key enzymes in the inflammatory signaling network. JNK-IN-8 is a covalent JNK inhibitor with IC50 values of 4.67, 18.7, and 0.98 nM for JNK1, JNK2, and JNK3, respectively. The EC50 values of JNK-IN-8 for the inhibition of c-Jun phosphorylation in Hela and A375 cells are 486 and 338 nM, respectively. JNK-IN-8 possessed a selective S (10) score of 0.031[3]. In P411-T1 patient-derived xenograft-derived cells, treatment with 1μM JNK-IN-8 for 24 h led to a significant decrease in p-JUN. JNK-IN-8 at 1 μM also enhanced the inhibitory effect of FOLFOX chemotherapy on cell growth and reversed FOLFOX-induced JUN activation in P441-T1, P442-T1, CFPAC-1, and MIA PaCa-2 cells. In mice bearing pancreatic ductal adenocarcinoma tumors, JNK-IN-8 (30 mg/kg, 2×/week) enhanced the efficacy of FOLFOX chemotherapy on tumor growth[4].
作用机制
JNK-IN-8 inhibits the kinase activity of JNK through the medication of a conserved cysteine in its ATP-binding motif[3].
JNK-IN-8 细胞实验
Cell Line
Concentration
Treated Time
Description
References
BV2 microglial cells
10 mM
JNK-IN-8 treatment inhibited the activation of BV2 microglial cells and reduced the expression of TNF-α, IL-1β, and IL-6
J Cell Physiol. 2020 Mar;235(3):2792-2799.
MDS-L cells
10 μM
To investigate the inhibitory effect of JNK-IN-8 on WFA-induced C-JUN phosphorylation, results showed that JNK-IN-8 pretreatment inhibited WFA-induced C-JUN phosphorylation.
Oncotarget. 2017 Aug 24;8(44):77436-77452.
WPMY-1 cells
2 μM
48 h
Inhibition of c-JUN phosphorylation, mimicking the effect of lactate on p62 expression.
Cell Rep. 2022 May 10;39(6):110792.
Normal human mammary epithelial cells
2μM
24 h
To test the effect of the JNK inhibitor on apoptosis of mammary epithelial cells in suspension culture, results showed that the JNK inhibitor strongly suppressed apoptosis induced by suspension culture.
Cell Rep. 2017 Nov 14;21(7):1910-1921.
PC-3 cells
1 μM and 2 μM
JNK-IN-8 counteracted the reduction in phosphorylation levels of JNK and C-Jun, induced by ASPA knockdown, in a dose-dependent manner
Mil Med Res. 2023 Jun 5;10(1):25.
SKMEL2 cells
200 nM
48 h
To study the effect of JNK-IN-8 on AP-1 activity, results showed that JNK-IN-8 suppressed AP-1 activity in NT cells but failed to rescue AP-1 activation in GRAMD1B knockdown cells.
Cancer Discov. 2023 Jan 9;13(1):194-215.
H1 hESCs
1 μM
1 day
JNK inhibitor treatment significantly improved DE differentiation efficiency and reduced differentiation variability
Nat Genet. 2019 Jun;51(6):999-1010.
HUES8 hESCs
1 μM
1 day
JNK inhibitor treatment significantly improved DE differentiation efficiency and reduced differentiation variability
Nat Genet. 2019 Jun;51(6):999-1010.
HUES6 hESCs
1 μM
1 day
JNK inhibitor treatment significantly improved DE differentiation efficiency and reduced differentiation variability
Nat Genet. 2019 Jun;51(6):999-1010.
BJ hiPSCs
1 μM
1 day
JNK inhibitor treatment significantly improved DE differentiation efficiency and reduced differentiation variability
Nat Genet. 2019 Jun;51(6):999-1010.
CV hiPSCs
1 μM
1 day
JNK inhibitor treatment significantly improved DE differentiation efficiency and reduced differentiation variability
Nat Genet. 2019 Jun;51(6):999-1010.
JNK-IN-8 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
NF2 LOF mutants-induced IOMM-Lee xenograft tumor model
Transient middle cerebral artery occlusion (tMCAO) model
Intraperitoneal injection
20 mg/kg
Single dose, 2 hours after MCAO
JNK-IN-8 treatment significantly improved neurological functional recovery in MCAO rats, inhibited microglial activation and JNK/NF-κB signaling pathway, and reduced the production of pro-inflammatory cytokines
J Cell Physiol. 2020 Mar;235(3):2792-2799.
Mice
SUM149 xenograft model
Intraperitoneal injection
15 mg/kg and 30 mg/kg
Daily for 34 days
JNK-IN-8 significantly suppressed tumor growth and reduced CSC phenotype
Oncogene. 2017 May 4;36(18):2599-2608
Mice
Abca4−/−Rdh8−/− mice
Intraperitoneal injection
4 mg/kg body weight
Once daily for 4 days
To evaluate the effect of JNK signaling inhibition on light-induced photoreceptor degeneration and apoptosis. Results showed JNK–IN-8 alleviated thinning of the photoreceptor layer, reduced apoptotic cells, and decreased protein levels of p-c-Jun, cleaved caspase-3, and γH2AX.
搜索
