Towards the discovery of Nurr1-RXR modulators

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The nuclear receptor transcription factor Nurr1 is essential for the regulation and maintenance of several important aspects of mammalian brain development and homeostasis. Nurr1 regulates a gene program that controls the development and function of dopaminergic neurons, which are critical for motor neuron function and control of movement that degenerates in patients with Parkinson’s disease. Furthermore, recent studies show that Nurr1 is an important factor in regulation of neuroinflammation and the accumulation of Amyloid beta (Aβ) that occurs in the pathogenesis of Alzheimer’s disease patients. These and other studies implicate small molecule activation of Nurr1 as a potential therapeutic strategy in Alzheimer’s disease, Parkinson’s disease, and other aging-associated neurodegenerative and dementia disorders characterized by a loss of neuron function. However, screening campaigns to discover Nurr1 binding and/or transcriptionally activating small molecules have produced limited Nurr1-specific compound scaffolds and have not yet provided potent, high affinity Nurr1-specific ligands. An alternative approach to regulate Nurr1 activity that has gained momentum is targeting Nurr1-RXR heterodimer complexes via small molecule ligands that bind to the RXR LBD. In this project, we will build on our strong preliminary data and develop biochemical and cellular assays that detect ligand-induced changes in Nurr1-RXR activity. The successful outcomes of our studies will provide a platform to screen, discover, and characterize Nurr1-RXR selective ligands that can be used as chemical tools to study Nurr1-RXR modulation in models of Alzheimer’s disease, Parkinson’s disease, and other aging-associated neurodegenerative and dementia disorders.