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Funded Studies

Identification and Characterization of Compounds that Regulate the Activity of the LRRK2 System

Study Rationale: Genetic mutations that lead to the activation of the enzyme LRRK2 are a major cause of inherited Parkinson's disease (PD). We have identified a protein, termed PPM1H, that counteracts the stimulation of the LRRK2 pathway. Our goal is to leverage the complementary technologies of two biotech companies (Evotec and WuXi) to identify and develop novel chemicals that boost the activity of PPM1H. Such compounds would be expected to reverse the disease-promoting effects of mutations in LRRK2 in people with PD.

Hypothesis: We hypothesize that chemicals with an ability to enhance PPM1H activity will repress the disease-causing activity of LLRK2, providing a new approach for treating PD.

Study Design: We will work with the company Evotec to painstakingly test its collection of 400,000 diverse compounds for molecules that stimulate PPM1H activity. At the same time, we will collaborate with the company WuXi to identify compounds that bind strongly to PPM1H from its collection of 15 billion small molecules. Candidates that emerge from these analyses will then be tested robustly to verify that they boost the activity of PPM1H. All compounds that activate PPM1H will be further characterized and studied.

Impact on Diagnosis/Treatment of Parkinson’s disease: This work has the potential to lead to a new approach for treating and preventing cases of PD caused by excessive activation of the LRRK2 network. The approach complements the work being undertaken to evaluate compounds that inhibit LRRK2 directly.

Next Steps for Development: If we succeed in identifying small molecules that boost PPM1H activity, the next stage of the project would involve partnering with pharmaceutical companies to further develop the compounds into potential drug candidates.


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