JNK-IN-8 is a specific JNK1/2/3 inhibitor with IC50 value of 4.67, 18.7, 0.98 nM respectively [1].
C-Jun N-terminal kinase (JNK) 1, 2 and 3 belong to the mitogen-activated protein kinase (MAPK) family, which are able to phosphorylate c-Jun on the Ser63 and Ser73 residue.They are responsive for stress stimuli, including cytokines and heat shock, and get involved in T cell differentiation and cell apoptosis process. JNK 1 and 2 are ubiquitous in all cell types but JNK 3 is only found in cells of brain, heart and testes tissues.
JNK-IN-8 is a JNK1/2/3 inhibitor with high specificity. When JNK-IN-8 was profiled with a panel of 400 kinases, it exhibited specific binding to JNK 1/2/3 but not to other kinases. Crystallization study also found that JNK-IN-8 forms covalent bonds with conserved cysteine residue of JNK 1/2/3, resulting in a conformational change of the activation loop that blocks the substrate binding, thereby inhibiting the activity of JNK 1/2/3 [1].
In Hela cells and A375 cells, pretreatment of cells with JNK-IN-8 resulted in the inhibition of c-Jun which is a direct phosphorylation substrate of JNK 1/2/3, confirming the inhibitory action of JNK-IN-8 on JNK 1/2/3. In HEK293-ILR1 cells following stimulation by anisomycin, the JNK-IN-8 was observed to inhibit c-Jun but not MSK1 and p38, and the inhibition was not reversible by removing JNK-IN-8 from culture medium. Additionally, JNK-IN-8 only exhibited on-pathway inhibition of JNK signaling pathway, which can be monitored by the phosphorylation of c-Jun [1].
Reference:
[1]. Zhang T et al., Discovery of potent and selective covalent inhibitors of JNK. Chemical Biology. 2012, 19(1):140-154.
