Mixedlineage kinase inhibitors

The c-jun JNK pathway leading to c-jun phosphorylation is involved in neuronal death in response to a wide variety of stimuli, including trophic factor withdrawal, Ab, MPTP glutamate, and NMDA toxicity. Although JNK is a target for preventing neuronal death, upstream kinases in this pathway, in particular, the MLKs are of interest.

CEP-1347 73 is an MLK inhibitor that blocks JNK signaling and has broad neuroprotective activity in a variety of in vitro and in vivo models of neuronal cell death.76 Of relevance to PD, CEP-1347 promotes survival of embryonic dopaminergic neurons77 and blocks MPP + induced cell death and MPTP-dependent increases in nigral JNK pathway activation and loss of SNpc DA neurons and striatal nerve terminals. Evaluation of CEP-1347 in a phase II/III trial for its ability to modify the course of PD showed no benefit of the NCE, and its development for PD was discontinued.75

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