Discovery of Novel Indazole Chemotypes as Isoform-Selective JNK3 Inhibitors for the Treatment of Parkinson's Disease.

c-Jun N-terminal kinases (JNKs) are involved in the pathogenesis of various diseases. In particular, JNK3 and not JNK1/2 is primarily expressed in the brain and plays a key role in mediating neurodegenerative diseases like Parkinson's disease (PD). Due to the sequence similarity of JNK isoforms, developing isoform-selective JNK3 inhibitors to evaluate their biological functions and therapeutic potential in PD has become a challenge. Herein, docking-based virtual screening and structure-activity relationship studies identified 25c with excellent inhibitory activity against JNK3 (IC 50 = 85.21 nM) and exhibited an over 100-fold isoform selectivity for JNK3 over JNK1/2 and remarkable kinase selectivity. 25c showed neuroprotective effects on in vitro and in vivo PD models by selectively inhibiting JNK3. Meanwhile, 25c showed an ideal blood-brain barrier permeability and low toxicity. Overall, this study provided a valuable molecular tool for investigating the role of JNK3 in PD and a solid foundation for developing JNK3-targeted drugs in PD treatment.