Mitogen-activated protein kinase 10 (JNK3) (JNK3)

Mitogen-activated protein kinase 10 (MAPK10), widely known as JNK3, is a serine/threonine-protein kinase that belongs to the c-Jun N-terminal kinase family. Unlike JNK1 and JNK2, which are ubiquitously expressed, JNK3 is predominantly localized in the brain, specifically within neurons of the hippocampus and neocortex (UniProt: P53779). It is a key mediator of neuronal apoptosis triggered by various stimuli, including amyloid-beta toxicity, oxidative stress, and glutamate-induced excitotoxicity (PubMed: 11084177). Consequently, JNK3 is considered a high-priority therapeutic target for neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, where its inhibition may offer neuroprotective benefits (PubMed: 22414704). Small molecule inhibitors typically target the ATP-binding site, though achieving selectivity over other JNK isoforms is a significant hurdle in clinical development (PubMed: 25853330). Beyond chronic neurodegeneration, JNK3 is also implicated in acute conditions like ischemic stroke and traumatic brain injury. The activation of JNK3 leads to the phosphorylation of c-Jun, which then promotes the transcription of pro-apoptotic genes. Research into JNK3 inhibitors also explores their potential in treating certain types of cancer and inflammatory conditions. Safety concerns primarily revolve around the potential for off-target effects on JNK1 and JNK2, which are essential for normal cell function and immune response. Future therapeutic success depends on the development of highly selective, brain-penetrant molecules that can effectively modulate this pathway without systemic toxicity.

Other names

c-Jun N-terminal kinase 3Stress-activated protein kinase JNK3SAPK1bPRKM10MAP kinase 10

ATP-competitive inhibition of the kinase domain to prevent phosphorylation of downstream substrates like c-Jun.