GNE-8505 (GNE8505) is a potent, selective and CNS-penetrant inhibitor of dual leucine zipper kinase (DLK, MAP3K12) with Ki of 3 nM.
GNE-8505 displays no significant inhibitory activity against a panel of 220 kinases (<70% inhibition at 1 uM), 42-fold selectivity over homologous mixed lineage kinase LZK based on binding affinity (Kd) values.
GNE-8505 reduces JNK phosphorylation (p-JNK) in HEK293 cells with IC50 of 0.195 uM, reduces p-MKK4 and p-JNK in models of chronic neurodegeneration.
GNE-8505 displays EC50 of 0.574 uM in a high-content in vitro axon degeneration assay.
GNE-8505 (15 or 50 mg/kg PO) reduces p-c-Jun in the PS2APP model of Alzheimer's disease.
