Characterization of an Inhibitor Compound of LRRK2 Function
MJFF Research Grant, 2010
LRRK2 (Leucine-Rich Repeat Kinase 2) is a protein thought to be involved in regulating signaling pathways in cells. Mutations in the gene for LRRK2 are associated with some familial forms of Parkinson’s disease (PD). A number of these pathogenic mutations in LRRK2 associated with PD have been found within a region of the protein, known as the kinase domain, a domain that normally functions to add chemical modifications to other proteins. The recent development of a compound that can selectively inhibit the kinase function of LRRK2 now enables scientist to more directly investigate the role of this protein in cellular systems, including other proteins it may modify. Ultimately, this may provide information about cellular pathways triggered in non-familial forms of PD pathogenesis as well.
When testing any novel compound, it is important for an investigator to know how selective it is for its target, in this case LRRK2 versus other proteins containing similar kinase domains. This analysis was conducted by Drs. Dario Alessi of the University of Dundee and Nathaniel Gray of Harvard University. As a follow-up, MJFF will work with a drug discovery company to evaluate the LRRK2 inhibitor compound (LRRK2-IN1) in a broad panel of assays to ensure that the compound is selective for LRRK2 and does not have any potential “off-target” effects.
MJFF will coordinate the distribution of this compound to scientists working on LRRK2 in MJFF’s LRRK2 Consortium. In addition, MJFF will work with CEREP have LRRK2-IN1 tested in a screen against a number of selective, central and peripheral therapeutically relevant targets. This large scale effort will facilitate a thorough characterization of the compound in a number of applications.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
A major obstacle in scientific progress is access to essential research tools. The LRRK2-IN1 compound may represent a critical pharmacological tool for studying LRRK2 function as well as a prototype for therapeutic molecules. In supporting this analysis, MJFF strives to accelerate LRRK2 research and therapeutic development.
This project will result in a more comprehensive understanding of a critical tool available to researchers to assess LRRK2 kinase function in a number of cellular pathways.
Location: New York, New York
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