JNK-IN-8 (Synonyms: JNK Inhibitor XVI)

JNK-IN-8 is the first irreversible JNK inhibitor that acts on JNK1, JNK2, and JNK3 with high specificity, with IC₅₀ values of 4.7 nM, 18.7 nM, and 1 nM in the A375 cell line, respectively^[1]. JNK-IN-8 forms a covalent bond with the conserved cysteine residue of JNK 1/2/3, causing a conformational change in the activation loop and blocking substrate binding, thereby inhibiting the activity of JNK 1/2/3^[1]. JNK 1, 2, and 3 are part of the mitogen-activated protein kinase (MAPK) family, capable of phosphorylating the Ser 63 and Ser 73 residues of c-Jun, responding to stress stimuli such as cytokines and heat shock, and involved in T cell differentiation and apoptosis processes.

In vitro, JNK-IN-8 inhibits c-Jun phosphorylation in HeLa and A375 cells, with EC₅₀ values of 486 nM and 338 nM, respectively^[1]. JNK-IN-8 also shows significant selectivity in HEK 293 cells^[1]. Additionally, JNK-IN-8 (10 mM) exhibits anti-inflammatory effects, reducing microglial activation and the expression of IL-6, IL-1β, and TNF-α^[2].

In vivo, JNK-IN-8 (20 mg/kg; i.p.) treated rats with middle cerebral artery occlusion show significant improvements in spatial learning and sensorimotor function recovery^[2]. Administration of JNK-IN-8 (3µg/µL) into the lateral ventricles of male KM mice 24 h before brain injury significantly reduces neuronal apoptosis after brain injury^[3].

References:
[1] Zhang T, Inesta-Vaquera F, et al, Discovery of potent and selective covalent inhibitors of JNK. Chemical Biology. 2012, 19(1):140-154.
[2] Geng W , Tang H , Dai Q ,et al. JNK-IN-8, a c-Jun N-terminal kinase inhibitor, improves functional recovery through suppressing neuroinflammation in ischemic stroke[J].Cold Spring Harbor Laboratory, 2018.
[3] Li D1, Liu N, et al, Protective effect of resveratrol against nigrostriatal pathway injury in striatum via JNK pathway. Brain Res. 2017 Jan 1;1654(Pt A):1-8.