Efficacies and Pharmacodynamic Assays for LRRk2 Small-Molecule Inhibitors

Duke University, Durham NC

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Abstract

No change from original application Parkinson disease (PD) is a common neurodegenerative disorder pathologically characterized by dopaminergic neurodegeneration and the spread of ?-synuclein (?-syn) inclusions through much of the brain. More than 10 million individuals worldwide are expected to have PD by the year 2030, and currently there are no accepted therapies that slow or halt the relentless progression of the disease. Dominant missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of PD, with up to 40 to 60 thousand carriers of the pathogenic G2019S-LRRK2 mutation in the United States. In model systems, the G2019S-LRRK2 mutation activates LRRK2 kinase activity. We and others have found that G2019S-LRRK2 expression exacerbates neurotoxicity and neuroinflammation associated with abnormal ?-syn, whereas knockout of LRRK2 expression protects from ?-syn. Recently, we demonstrated that pharmacological inhibition of LRRK2 kinase activity using a novel small molecule LRRK2 kinase inhibitor PF-475 provided substantial neuroprotection from ?-syn. In this research proposal, we request support to study the effects of two structurally distinct but equally potent LRRK2 kinase inhibitors in three key areas we believe are necessary for the successful development of clinical candidate LRRK2 kinase inhibitors. First (R21 phase), we will define pharmacokinetic and dynamic parameters in blocking wild-type and G2019S-LRRK2 kinase activity in the rodent brain. In the process, we will further develop reliable target engagement assays for LRRK2 kinase inhibition that can be translated to clinical approaches. Second (R33 phase), using our dosing strategies identified in the R21 phase, we will define efficacious doses (EDs) for neuroprotection from ?-syn fibril-induced neurodegeneration in rats. We hypothesize that it may not be necessary to completely inhibit LRRK2 kinase activity to realize therapeutic effects, and lower compound doses and incomplete LRRK2 kinase inhibition may increase therapeutic benefit by limiting undesirable effects. Third (R33 phase), we will vary the timing of compound administration to determine efficacies in blocking toxicities after ?-syn aggregation and neurodegeneration has already initiated. We predict that better characterization of LRRK2 kinase inhibitor efficacies and dosing strategies in both early and later-phases in ?-syn aggregation and neurodegeneration may predict the therapeutic benefits of LRRK2 kinase inhibitors and amount of kinase inhibition required for success in early versus established PD.