Identification of Nurr1/RXR complex agonists for neuroprotection
Université de Montréal
Numerous scientific evidences converge to indicate that the transcription factor complex (modulator of gene expression) formed by Nurr1, and its partner retinoid X receptor (Nurr1/RXR), represents an interesting new drug target for neuroprotection in the context of Parkinson’s disease. Indeed, 1) Nurr1/RXR complex is essential for the development and post-natal maintenance of dopamine neurons, which prematurely degenerate in Parkinson’s disease. 2) Partial genetic deletion of Nurr1 renders dopamine neurons more vulnerable to neurotoxins. 3) Mutations in the Nurr1 gene in human suggest that impaired Nurr1 function may increase vulnerability of dopamine neurons to degeneration. 4) Nurr1/RXR transcriptional activity regulates the expression of genes involved in dopamine metabolism and turnover, trophic support of dopamine neurons, inflammatory response in the brain and mitochondrial activity. All these activities have been proposed to play a role in the death of dopamine neurons. Unfortunately, there is currently no available selective drug targeting this nuclear receptor complex. So, the general objective of the research project is to identify new compounds showing potency and selectivity for the activation of Nurr1/RXR nuclear receptor complex. To achieve this goal, we have developed new highly sensitive sensors that can detect recruitment of a co-activator by specific receptor dimers in live cells and in real time. These assays combine the Bioluminescence Resonance Energy Transfer (BRET) and luciferase Protein fragment Complementation Assay (PCA) technologies to enable simultaneous detection of interactions between three partners (Nurr1/RXR complex dimerization and co-regulator recruitment by the complex). Using this new assay, we will screen 2 libraries of compounds (over 200,000 compounds) from 2 different screening platform facilities. Hit compounds will be confirmed and validated and selectivity of the confirmed hits will be tested.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
The relevance to the acceleration of therapeutics for neurodegenerative diseases of aging of the present drug discovery program should be important. Nurr1/RXR receptor complex is considered as one of the most promising candidate target for neuroprotection in Parkinson’s disease. The compounds generated within this program could be rapidly used to validate neuroprotective activity associated with the activity of this target and its disease modifying properties in both in vitro and in vivo experimental Parkinson’s disease.
The new technology/assay developed by our team, that will be used to screen libraries of compounds, will identify new chemical entities which are able to interact with the target. So, we should identify, for the first time, new and original compounds that selectively modulate Nurr1/RXR complex activity.