Design and Synthesis of a Mitochondrial-Targeted JNK Inhibitor and Its Protective Effect on Parkinson's Disease Phenotypes.

C-Jun N-terminal kinase (JNK) is a key mediator involved in a variety of physiological processes. JNK activation is regulated in a complex manner by upstream kinases and phosphatases, and plays an important role in physiological processes such as the immune response and neuronal function. Therefore, JNK has become a therapeutic target for neurodegenerative diseases, ankylosing spondylitis, psoriasis, arthritis and other diseases. Inhibition of JNK activation in mitochondria holds great potential for Parkinson's disease (PD) therapy. However, no specific mitochondrial-targeted JNK inhibitor has been reported. We have developed a mitochondrial-targeted JNK inhibitor, P2, by linking a mitochondrial-specific cell-penetrating peptide to SP600125 (SP), a commercialized specific inhibitor of JNK. We found that P2 specifically inhibited mitochondrial JNK phosphorylation instead of nuclear JNK signaling. Further studies showed that P2 effectively rescued PD phenotypes both in vitro and in vivo, thus indicating that it is a potential therapeutic for PD.