Nurr1 is a protein that plays critical roles in the development, maintenance and survival of dopaminergic neurons and, as such, is a potential therapeutic target for treating the symptoms and progression of Parkinson’s disease. Efforts to develop drugs that stimulate Nurr1 activity have been hampered by the absence of a well-defined binding site for small molecules. Recently, though, we found a small molecule that we have shown stimulates Nurr1 activity. This study seeks to improve the affinity and efficacy of this compound for pre-clinical studies.
We aim to demonstrate that small molecules possessing specific pre-clinical attributes (nanomolar affinity, cellular efficacy, good solubility and stability, non-toxic, selective) can be developed and used to directly stimulate the transcriptional activity of Nurr1.
Small molecules that activate Nurr1 will be developed using iterative cycles of medicinal chemistry, biophysical binding assays and target gene transcription assays. Starting with our crystal structure of a Nurr1 agonist bound to the receptor, we will generate ~50 analogs of this lead compound using standard medicinal chemistry, determine the binding affinity of the analogs using direct binding assays, measure the effects of the analogs on the expression of genes underlying the synthesis and packaging of dopamine, evaluate the toxicity and selectivity of the compounds, and characterize the pharmacokinetics (solubility, stability, permeability) of the top two analogs.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Activation of Nurr1 is an alternative to current methods for increasing dopamine levels, which may prevent motor symptoms. Further, Nurr1 may slow the progression of the disease owing to the important roles the receptor plays in the maintenance and survival of dopaminergic neurons.
Next Steps for Development:
Following successful identification of a compound with appropriate cellular properties, we will study the compound in Parkinson’s models. In particular, we will determine compound permeability through the blood brain barrier and impact on dopamine levels in the brain.