GNE-3511

GNE-3511 is a selective and highly potent inhibitor of dual leucine zipper kinase (DLK), also known as MAP3K12 (K_i = 500 pM).¹ It also inhibits phosphorylated JNK (IC₅₀ = 30 nM) and is highly selective for DLK over other MAP kinases (IC₅₀ > 5,000 nM for MKK4 and MKK7), JNKs (IC₅₀s = 129, 514, and 364 nM for JNK1, JNK2, and JNK3, respectively), and mixed-lineage kinases (MLKs; IC₅₀s = 68, 767, and 602 nM for MLK1, MLK2, and MLK3, respectively). GNE-3511 protects primary neurons in an in vitro axon degeneration assay (IC₅₀ = 107 nM). In an MPTP mouse model of Parkinson’s disease, a high dose of GNE-3511 (75 mg/kg) completely suppresses phosphorylated c-Jun (p-c-Jun) expression, while a low dose (37.5 mg/kg) moderately reduces its expression.