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Funded Studies

Development of Small Molecule Activators of Nurr1 as Potential Therapeutics for Parkinson's Disease

Study Rationale: Parkonson’s disease (PD) is characterized by neuroinflammation and the death of dopamine-producing neurons. Nurr1 is a protein that regulates the activity of genes to reduce inflammation, stimulate dopamine synthesis, and promote the survival of these vulnerable cells. These critical activities make Nurr1 an attractive molecular target for treating the symptoms and progression of PD. We recently produced high-resolution structures that show how two different small molecules, each of which stimulates Nurr1 activity, bind to the surface of the protein. In this proposed study, we seek to improve the affinity and efficacy of these two Nurr1-activating molecules for preclinical studies.

Hypothesis: We hypothesize that we can develop small molecules possessing desirable preclinical attributes (high affinity, efficacy, solubility, stability and selectivity with low toxicity) that stimulate Nurr1, boosting the activity of genes required for the synthesis and secretion of dopamine (compound 1) and repressing the activity of neuroinflammatory genes (compound 2).

Study Design: We will develop our small molecule Nurr1 activators using iterative cycles of medicinal chemistry, biophysical assays to measure binding and transcription assays to assess gene activation. One of our lead molecules stimulates the activity of genes required for the synthesis and release of dopamine, the other represses the activity of genes that promote neuroinflammation. Molecules that display suitable binding affinity and efficacy in cultured cells will be further characterized in terms of their toxicity, selectivity and pharmacokinetics (including solubility, stability and permeability). The top molecule emerging from these studies will be tested in a preclinical mouse model of PD.

Impact on Diagnosis/Treatment of Parkinson’s disease: The current gold-standard therapeutic for treating PD, Sinemet (Carbidopa-Levodopa), reduces symptoms by providing the brain with dopamine; however, this drug also produces side effects, including involuntary movements called dyskinesias. By enhancing survival of dopamine-producing cells and reducing their neuroinflammation-induced degradation, Nurr1 activation may boost dopamine levels without inducing dyskinesias.

Next Steps for Development: We will continue to assess our successful Nurr1 activators for their ability to enhance dopamine and reduce symptoms in additional preclinical animal models of PD, including those in which the degeneration of dopamine-producing neurons is induced by chemical treatment or by a toxic aggregation of alpha-synuclein. 


Researchers

  • Pamela M. England, PhD

    San Francisco, CA United States


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