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Discovery of Novel Inhibitors of LRRK2 for the Treatment of Parkinson's Disease

Objective/Rationale: 
A recent breakthrough in Parkinson’s disease research is the discovery that mutations in the gene for leucine-rich repeat kinase 2 (LRRK2) are associated with both the hereditary and sporadic late-onset forms of the illness. The most common mutation, G2019S, is in the active site of the LRRK2 kinase domain. Since G2019S activates LRRK2 kinase, an inhibitor for this mutant is likely to provide an effective treatment for PD.
Project Description:
The goal of this program is to identify compounds that specifically inhibit the activity of LRRK2 to be used to validate it as a PD target. Phase I of the program is focused on determining the three dimensional structure of native and mutant LRRK2. Comparison of the structures may yield information relevant to disease progression and will be an important starting point for discovery of a treatment. The method of fragment-based lead discovery will be applied to this target. Here, fragments of drugs are screened and their binding mode determined by visualization through X-ray crystallography. The fragments are then re-combined into novel compounds that bind specifically to the target of interest. These compounds will be tested in neuronal cell assays and in animal models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
LRRK2 inhibitors may provide the first direct treatment or cure for PD. These compounds are expected to specifically block the disease causative agent rather than providing non-specific symptom relief obtained with L-dopa and inhibitors that block its metabolism. This is analogous to the use of specific kinase-targeted cancer therapies, which have essentially cured diseases such as CML, and contrasts with traditional chemotherapeutic compounds that are non-specific and, in general, are less effective.
Anticipated Outcome: 
This work will yield the crystal structure of native and mutant LRRK2. The structure may be broadly used in PD research. LRRK2 inhibitors will be used to validate LRRK2 as a PD target and may lead to identification of additional targets and pathways relavent to disease progression. Most importantly, these inhibitors may lead to a cure for PD.

Final Outcome

Dr. Nienaber has made progress in establishing the research tools necessary for her project.


Researchers

  • Vicki L. Nienaber, PhD

    San Diego, CA United States


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