DLK (dual leucine zipper kinase, MAP3K12) is identified as an essential regulator of neuronal degeneration in multiple contexts, as loss of DLK expression resulted in protection of retinal ganglion cell neurons from degeneration as well as an attenuation of downstream signaling, following injury. GNE-3511 is a potent, selective and brain-penetrant DLK inhibitor with Ki value less than 0.5nM. Suppression of DLK through GNE-3511 led to inhibition of p-JNK and primary rat dorsal root ganglion (DRG) neurons in an in vitro axon degeneration assay with IC50 values of 30nM and 107nM, respectively. GNE-3511 exhibited very good selectivity over the other JNK pathway kinases and homologues of DLK, with IC50 values of 129, 514, 364, 67.8, 767 and 602nM for JNK1, 2, 3, MLK1, 2, 3, respectively, as well as >5000nM for both MKK4 and 7. Oral administration of GNE-3511 30min prior to nerve crush injury dose-dependently reduced p-c-Jun level induced by injury, as a pharmacodynamics readout of DLK inhibition in vivo, in retina of a Nerve Crush model at dose of 25mg/kg and 75mg/kg, and in dopaminergic neurons of the substantia nigra in a MPTP-induced Parkinson’s disease model at dose of 37.5 and 75mg/kg.
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