Objective/Rationale:
Zenobia Therapeutics has identified a unique series of highly specific and potent LRRK2 inhibitors with central nervous system drug-like chemical properties using the method of fragment-based drug discovery. These compounds show positive in vivo properties and in vitro toxicity. However, they have not been fully characterized. The goal of these studies is to fully characterize this series of compounds in advanced in vivo and in vitro toxicity studies. Positive results will lead to advancement into late stage optimization and pre-clinical studies.
Project Description:
To progress a compound into clinical trials, a number of pre-clinical tests must be run to ascertain any potential issues in toxicity or effectiveness. Zenobia’s series is ready to progress into these types of tests. To determine if the compound is stable and able to reach the target of interest in the brain, a series of in vitro and in vivo tests will be run.
In vitro experiments will determine the metabolic stability of our compounds in pre-clinical models and humans, permeability into the brain, and available fraction of drug in brain to bind to target. Compounds will also be characterized in models to determine the concentration of compound in the plasma and brain over time. We will also analyze for inhibition of LRRK2 in the brain. The best compound will be tested for predicted toxicity in the clinic. Compounds will be analyzed for hERG binding, which can lead to cardiac issues, and CYP inhibition, which can lead to drug-drug interaction. Geneotoxicity will also be analyzed. Selectivity will be fully characterized by testing against a general brain receptor panel and extended kinase panel.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
G2019S LRRK2 is the most common hereditary mutation in Parkinson’s disease, resulting in increased activity of the enzyme. Hence, inhibition of this enzyme is expected to result in neuroprotection. The approach is to treat G2019S LRRK2 patients in advance of symptom onset with a goal of halting or delaying progression of the disease. The target is also implicated in sporadic disease.
Anticipated Outcome:
Through these studies, we will identify the strengths and weaknesses of our current series indicating how close we are to a clinical candidate. This will aid in design of future studies and in identifying pharmaceutical company partners to advance our program into the clinic.