Objective/Rationale:
LRRK2 is well recognized as a potential central nervous system target for the treatment of Parkinson’s disease (PD). For development as possible therapeutic drugs, Genentech has produced highly potent and selective small molecules that inhibit the kinase activity of LRRK2 (Chen et al., J Med Chem 2012; Estrada et al., J Med Chem 2012). A published description of genetically modified pre-clinical models with no LRRK2 protein expression or with LRRK2 mutations altering its kinase function, suggests that targeting LRRK2 outside of the brain may result in undesired effects to kidney, lung, and blood pressure (Herzig et al., Hum Mol Genet 2011). The goal of this project is to further an early understanding of the safety liabilities of LRRK2-targeted small molecule inhibitors.
Project Description:
We plan to conduct a safety study in pre-clinical models with LRRK2 kinase small molecule inhibitors and characterize any adverse findings.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
An acceptable safety profile would allow further advancement of LRRK2-targeted small molecules as drug candidates. LRRK2-targeted drugs could provide a novel therapeutic mechanism for the treatment of Parkinson’s disease.
Anticipated Outcome:
The goal of this project is to further a broader understanding of the safety liabilities of LRRK2 kinase inhibitors that are being considered for the treatment of Parkinson’s disease.