Development of GSK-3 Beta Inhibitors for the Treatment of Parkinson's Disease
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PSYCHOGENICS, INC. (Currently PSYCHOGENICS, INC.)
*(FY 08 USE 4147301), TARRYTOWN, NY, 10591
AbstractDESCRIPTION (provided by applicant): Parkinson's disease (PD), a chronic and progressive neurological condition and one of aging and age- related diseases, affects approximately 1.5 million people in the US alone. PD not only places severe burden on the pa tients but also on their family and society. In 2003, approximately US 2.3 billion was spent on drug therapy worldwide to treat Parkinson's disease. Although great strides have been made in the development of agents to treat PD, the existing PD drugs such as dopamine (DA) agonists, levodopa and catechol-O-methyl transferase inhibitors (COMT) only treat the symptoms of the disease, and are also fraught with adverse effects and long-term complications. Consequently, there is a great need for developing disea se-modifying and neuroprotective as well as neurorestorative drugs which can slow down or stop the disease from progressing. Recent research suggests that inhibition of the glycogen synthase kinase-3a (GSK-3a) by small molecules may offer an important stra tegy in the treatment of a number of neurodegenerative diseases including Alzheimer's disease (AD), but its usefulness in PD has not been described. We have recently found in the cellular and animal MPTP model of parkinsonism, an induction in the hyperphos phorylated form of Tau, p-Tau, with hyperphosphorylation seen at many sites, including those found in neurofibrillary tangles of AD. The increase in p-Tau levels was strictly dependent upon the presence of a- Syn. This requirement for a-Syn was mandatory, since in a-Syn-/- mice, and in transfected cells not expressing any a-Syn, the toxin failed to induce p-Tau. MPTP also caused an increase in a-Syn protein levels. Hyperphosphorylation of Tau lead to its dissociation from the cytoskeleton, and aggregates of p-Tau were seen in sarkosyl-insoluble and Triton X-100-insoluble fractions. a-Syn was able to form stable heteromeric protein complexes with p-Tau, and p-Tau aggregates were seen in mature inclusion bodies of a-Syn. MPP+ caused the activation of several p -Tau-specific kinases, such as GSK-3a and p-ERK. Blockade of GSK-3a not only prevented, but also reduced, MPP+-induced p-Tau formation, a-Syn accumulation and cytotoxicity. Very new data obtained in human postmortem PD brains, in collaboration with Dr. Jef frey Joyce, show a similar pattern of pathology: increased a-Syn accumulation, hyperphosphorylation of Tau at sites similar to the MPTP models [pSer262 and pSer396/404], lack of phosphorylation at sites not seen with MPTP [pSer202], and large increases in GSK-3a. Interestingly, these pathological changes were further augmented in PD patients with dementia [PD + DEM]. Together, these findings in PD brains confirm the validity of our findings with the MPTP models. Importantly, prior to our findings, a possibl e role for GSK-3a in PD has not been previously described, although its role in AD is well studied. In addition to our findings, another study found strong linkage of two single nucleotide polymorphisms in the GSK-3a gene to sporadic PD. Thus, GSK-3a prese nts a novel target site in the development of novel therapies for PD. To date, we have identified some nM potency GSK-3a inhibitors that emerged from our SAR studies of staurosporine. A number of these designed staurosporine analogs have been screened agai nst a family of 30 kinases. Among the compounds tested we found one, an indolyl-indazolylmaleimide, that was able to inhibit 98% of the kinase activity of GSK-3a when tested at a concentration of 10 fM. After further structural modifications described belo w, novel 3-(indol-3-yl)-4-(benzofuran-3-yl)maleimides having a Ki value as low as 2 nM selectively against GSK-3a relative to 30 additional kinases were identified. Moreover, we have been able to show that some of these ligands are able to exert a neuropro tective and neurorestorative action in vitro. The ultimate goal would be to identify one or two GSK-3a inhibitors that could be further developed for slowin
* information listed above is at the time of submission.