GNE-3511

GNE-3511 (CAS No.: 1496581-76-0) is a highly potent, selective small-molecule inhibitor of dual leucine zipper kinase (DLK, also known as MAP3K12), a key upstream regulator of neuronal stress and degeneration signaling pathways. It exhibits sub-nanomolar binding affinity for DLK and effectively suppresses downstream c-Jun N-terminal kinase (JNK) pathway activation, including inhibition of phosphorylated JNK at low nanomolar concentrations, while maintaining strong selectivity over related MAP kinase family members such as MKK4/7, JNK isoforms, and mixed-lineage kinases. Functionally, GNE-3511 modulates DLK-mediated signaling cascades implicated in axonal injury responses and neurodegeneration, demonstrating neuroprotective effects in primary neuronal cultures with activity in the nanomolar range in axon degeneration assays. In vivo, it is orally bioavailable and capable of penetrating the blood–brain barrier, enabling effective target engagement in central nervous system models, where it has been shown to suppress phosphorylation of c-Jun in toxin-induced models of Parkinson’s disease. This compound is widely used as a pharmacological tool in studies of neurodegenerative disease mechanisms, axonal biology, and kinase signaling, with experimental concentrations or dosing regimens typically optimized according to specific cellular or animal model systems.