The MLK inhibitor, CEP11004: A candidate for the treatment of Parkinson’s disease

The aging population will contribute to an expansion of the already $30 billion neurodegenerative disease market. The market for Alzheimer disease therapy is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Between 2005 and 2010, drugs for treating Alzheimer disease could achieve sales of well over $2 billion.

Parkinson's disease also represents a considerable component of the neurodegenerative disease market affecting some four million people worldwide. It is a progressive disorder of movement characterized by a progressive loss of dopamine neurons in the pars compacta of the substantia nigra and various extrapyramidal features including resting tremor, rigidity, bradykinesia, postural instability, and freezing. The current worldwide market for the treatment of Parkinson's disease is estimated to be approximately $1.5 billion with an estimated annual growth of 10% (click here for “Neurodegenerative Disorders: World Markets 2002-2007” which provides a full analysis of this field).

Apoptosis or programmed cell death may play a role in the pathogenesis of the chronic neurodegenerative diseases and so may provide a target for therapeutic interventions. The apoptosis pathway involves the activation of the caspase cascade, a family of cysteine proteases that execute the apoptotic pathway.

The three main programmed cell death pathways identified thus far (the mitochondrial, endoplasmic reticulum (ER) stress, and death receptor pathways) are activated by upstream caspases-9, -12, and -8, respectively. The mitochondrial pathway may also serve as a point of convergence for the other two pathways, since death receptor activation and ER stress can both lead to cytochrome c release from the mitochondria and subsequent caspase-9 activation. Once cleaved caspase-9 activates caspase-3, the primary downstream executioner caspase although this caspase is also activated independently of the mitochondrial pathway by, for example, caspase-8.

Therapeutic interventions may be more effective if they act up-stream in death pathways. One up-stream signaling cascade that mediates cell death is that of c-jun N-terminal kinase (JNK) phosphorylation of c-jun. Programmed cell death in neurons can be inhibited by neutralizing antibodies to c-jun or by dominant negative mutants. JNK activity is, in turn, regulated by a complex up-stream kinase cascade, many components of which have also been implicated in the regulation of neuronal cell death in vitro. This signaling cascade is likely to be up-stream of mitochondrial release of death mediators because inhibition of death with a dominant negative c-jun blocks cytochrome c release in vitro.

CEP1347 is a mixed lineage kinase (MLK) inhibitor which suppresses death induced by various stimuli including beta-amyloid supporting its development for the treatment of Alzheimer’s disease. In a recent study Ganguly et al report the effect of another MLK inhibitor, CEP11004, on apoptotic death of dopamine neurons of the substantia nigra in order to investigate the potential of MLK inhibitors to treat Parkinson’s disease. The authors use a model of cell death that is exclusively apoptotic and which is associated with activation of caspase-9.

Injection of 6OHDA into the striata of neonate rats increased the expression and phosphorylation of c-jun in substantia nigra pars compacta dopaminergic neurons. The suppression of MLKs in these cells by orally administered CEP11004 resulted in a near 50% reduction in cell death and in caspase-9 activity; efficacy was not improved by increasing the dose of CEP11004. Of note CEP11004 preserved dopamine neurons as well as their terminal axonal structures. This is important clinically because striatal dopaminergic terminal markers are reduced out of proportion to cell body loss in Parkinson’s disease, leading to suggestions that terminal structures may suffer the brunt of pathology early in the course of the disease.

These data suggest that MLK inhibition by CEP11004 can reduce neuronal cell death in a model of Parkinson’s disease. Although this effect was incomplete, suggesting that MLKs are important but not critical in mediating neural death in this model, CEP11004 and similar molecules deserve further evaluation in the context of Parkinson’s disease.

Cancer, rheumatoid arthritis, diabetes, cardiovascular disease, neurological disorders, and as many as 400 other conditions have been linked to kinase activity. All of these represent potential blockbuster markets, in the $1–7 billion range and thus a large number of pharmaceutical and biotech companies have active kinase research programs (click here for a full analysis of kinase research activity and commercial potential). The present study underlines the potential of MLKs and especially CEP11004 which is now in clinical trials for Parkinson's disease.

Readers who are interested in developing novel MLK inhibitors should be aware of the “Kinase Enterprise Library” that LeadDiscovery has recently featured. This is a targeted library of candidate kinase inhibitors that is available for in house screening. Alternatively, options are available through which LeadDiscovery’s partner ChemOvation can dock this library into the active sites of MLKs using their suite of computational tools (Click here for further information on this library).

Entry date Sunday, April 18, 2004

Adapted from Burke et al, J Neurochem. 2004 Jan;88(2):469-80