A potential avenue for therapeutic intervention is kinases linked to abnormal phosphorylation of tau, which is implicated in Alzheimer disease. [Andrea Danti - Fotolia.com]
Protein kinases (PK) have provided drug targets that have yielded innovative and highly effective therapeutics for cancer treatment. These include small molecule PK inhibitors such as Novartis’ Gleevec, Pfizer’s Sutent, GlaxoSmithKline’s Tykerb, and Bristol-Myers Squibb’s Sprycel. PK inhibitors now comprise over 30% of most major pharmaceutical companies’ pipelines. By 2020, small molecule kinase inhibitors are expected to collectively generate annual revenues of over $25 billion.
The success of kinase inhibitors in cancer has spurred research to develop similar compounds for other diseases including neurodegenerative disorders. But how close to the clinic are kinase inhibitors for central nervous system (CNS) diseases? Noscira has one drug candidate that is in Phase II for supranuclear palsy and is also ready to enter mid-stage trials in Alzheimer disease (AD).
Plenty of basic research, however, is being conducted. As the significance of kinases in the molecular pathway of neuronal survival becomes more apparent, multiple different key pathways are being described, leading to a plethora of potential targets.
Pathways of interest for CNS diseases “include apoptotic and necrosis pathways as well as pathways involving inflammation since this is also a factor that exacerbates cell loss in neurodegenerative diseases,” Marcie Glicksman, Ph.D., co-director of the lab for drug discovery in neurodegeneration, Harvard NeuroDiscovery Center, told GEN.
Dr. Glicksman further noted that other kinase-regulated dysfunctional pathways including mitochondrial dysfunction, protein misfolding and aggregation, as well as abnormal RNA processing may all be fair game as viable drug targets for neurodegenerative disorders.
Another potential avenue would be kinases involved in abnormal phosphorylation of tau, which is linked to AD. Additionally, mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) that are known to lead to Parkinson disease (PD) are also viable target candidates, Dr. Glicksman reported.
Tau Phosphorylation Research
Aggregation of hyperphosphorylated tau characterizes neuropathological lesions in diseases like AD. Recent studies support that disease-associated changes in soluble tau, including phosphorylation, occur relatively early and are involved in the induction of neuronal death.
Scientists caution, though, that while numerous reports have produced a huge amount of information about the activities of specific kinases on tau, the “identities of the true physiological and pathological kinases in vivo remain unknown.” Several strategies to mitigate tau phosphorylation, including disaggregation of tau inclusions and tau immunotherapy, can be pursued investigators have remarked.
Phosphorylation reduction through inhibition of specific protein kinases, however, remains of interest to many scientists as a viable strategy. Inhibition of proline-directed protein kinases such as glycogen synthase kinase-3 (GSK-3) and cyclin dependent kinase-5 (CDK-5) have been studied in transgenic animal studies. Other candidate kinases impacting tau hyperphosphorylation that may serve as potential drug targets include the extracellular signal-regulated kinase ERK2, casein kinase 1.
GSK-3beta has been implicated in multiple cellular processes and linked with pathogenesis of and neuronal loss in several neurodegenerative diseases including Parkinson and Huntington diseases. Studies have shown that the enzyme’s overexpression in transgenic mouse models results in increased tau phosphorylation and deficits in spatial learning. Inhibition of GSK-3beta activity leads to neuroprotective effects, decreased amyloid-beta production, and a reduction in tau hyperphosphorylation.
CDK-5, on the other hand, is required for the development of the central nervous system through regulation of neuronal migration. One of its activators, p25, is increased in AD brains where p25 and CDK-5 are co-localized with neurofibrillary tangles.
Several animal models have shown a correlation of p25/CDK-5 activities with tau phosphorylation. Overexpression of p25/CDK-5 in neuronal cultures not only leads to tau phosphorylation but also cytoskeletal abnormalities and neurodegeneration.
Noscira is the only company with a clinical-stage kinase inhibitor for a neurodegenerative disease, however. Its candidate, a small molecule GSK-3beta inhibitor called tideglusib, has orphan drug designation in the EU and fast-track status in the U.S. Last October Noscira said it had completed recruitment for its Phase II trial in supranuclear palsy.
In Alzheimer disease Noscira received approval in April to begin a Phase IIb trial. The company says that the compound has proven active against all of the histopathological lesions associated with the disease in experimental models: It reduces phosphorylation of the tau protein and hippocampal and entorhinal cortex neuron loss, improves spatial memory deficits, and reduces the accumulation of amyloid plaques in the brain. It also provides neuroprotection in vivo and has an anti-inflammatory effect in a range of animal models, the firm adds.
A Phase IIa trial in Germany was completed in early 2010. It was designed with the primary goal of assessing the safety and tolerability of the molecule. The company reported that the drug was well tolerated and had “a positive effect on patients’ cognitive performance”, although the results were not statistically significant “due to the small sample size and short treatment period.”
Besides tau another approach for kinase inhibitor development for neurodegenerative diseases is targeting LRRK2. As of February 2010, The Michael J. Fox Foundation for Parkinson’s Research had invested nearly $17 million to drive related initiatives at every stage of drug development. First linked to PD in 2004, mutations in the gene LRRK2 have recently been associated with autosomal dominant, late-onset PD that is clinically indistinguishable from typical, idiopathic disease.
LRRK2 is a multidomain protein containing several protein interaction motifs as well as dual enzymatic domains of GTPase and protein kinase activities. Disease-associated mutations are found throughout the multidomain structure of the protein. Researchers say that LRRK2 is unique among PD-causing genes because a missense mutation known as G2019S is a frequent determinant of not only familial but also sporadic PD.
The recent development of a compound that can selectively inhibit the kinase function of LRRK2 may enable scientists to more directly investigate the role of this protein in cellular systems, including which other proteins it may modify. Although unlikely to provide a therapeutic option for PD because it doesn’t cross the blood brain barrier, the molecule will help provide information about cellular pathways triggered in nonfamilial forms of PD pathogenesis as well.
While only one kinase inhibitor targeting neurodegenerative disorders has reached the clinic to date, vast efforts to sift through relevant pathways and identify inhibitors of kinases thought to be involved in these diseases are under way. It is hoped that this basic research will give way to preclinical development and eventually testing in humans, but that’s a fairly long way off.