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Funded Studies

Synthetic Nurr1 Ligands as Novel Neuroprotective Therapeutics to Treat Parkinson’s Disease

Objective/Rationale:             
The orphan nuclear receptor Nurr1 plays a critical role in the development and maintenance of midbrain dopamine neurons. Recent research also shows that it protects midbrain dopamine neurons from neuroinflammation-induced death. Therefore, Nurr1 activators may be promising agents for the treatment of Parkinson’s disease (PD). Based on encouraging preliminary data from our laboratory, we propose to identify and characterize small molecules that can activate Nurr1 with the long-term goal of delivering a safe and effective neuroprotective therapy for PD.

Project Description:             
To identify activators of Nurr1, we have established efficient cell-based assays as well as counter assays to help distinguish non-specific effects. In support of our project, we identified three compounds with an identical chemical scaffold that activate Nurr1, strongly suggesting a critical structure-activity relationship. Based on this relationship, we will generate new chemical derivatives sharing the identical scaffold and test their in vitro and in vivo efficacy, pharmacological properties and safety. We will perform iterative cycles of medicinal chemistry and repeat assays to identify the most promising drug candidates, which will then be tested in pre-clinical models of PD.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Although currently available PD drug therapies have been crucial to improve the quality of life of many patients, they unfortunately only offer symptomatic relief. In addition, the need for more frequent and higher doses of dopaminergic agents can reach clinical limits, including severe side effects such as involuntary movement (dyskinesia). In this regard, successful identification of small molecules that can effectively activate Nurr1 function could lead to a paradigm shift by introducing a neuroprotective treatment of PD.

Anticipated Outcome:          
Nurr1 is considered to be a promising drug target for PD, but many researchers believe that Nurr1 is ligand-independent and constitutively active. However, our laboratory has recently identified several small molecules containing an identical scaffold that activate Nurr1 by directly interacting with its ligand-binding domain. For this reason, the further identification of optimal compounds will not only advance our understanding of Nurr1 biology but could also directly result in the development of novel therapeutic agents that work through Nurr1 activation.

Final Outcome

To identify and characterize small molecules that can activate Nurr1, we established efficient cell-based assays, screened an FDA-approved drug library, and identified three compounds (amodiaquine, chloroquine, and glafenin) with an identical chemical scaffold that activate Nurr1, strongly suggesting a critical structure-activity relationship (SAR).  Remarkably, we found that these chemicals enhance the transcriptional activities of Nurr1 via direct binding to its ligand-binding domain, rendering Nurr1 an adopted nuclear receptor. Furthermore, we found that amodiaquine can improve motor behavioral deficits in 6-OHDA pre-clinical models in a neuroprotective manner.  

Based on these results, we generated >400 chemical derivatives sharing this identical scaffold and identified promising candidates with EC50 in the nanomolar range (that is, 100-1,000-fold lower than that of amodiaquine or chloroquine). 

In summary, we showed, for the first time to our knowledge, proof-of-principle data that it is possible to identify small molecules that can activate Nurr1 via its ligand-binding domain for mechanism-based and neuroprotective therapeutic development of PD.  

Publications

Kim, C., Han, B.-S., Moon, J., Kim, D.-J., Shin, J., Rajan, S., Nguyen, Q.T., Sohn, M., Kim, W.-G., Han, M., Jeong, I., Kim, K.-S., Lee, E.-H., Tu, Y., Naffin-Olivos, J.L., Park, C.-H., Ringe, D., Yoon, H.S., Petsko, G.A., and Kim, K.S. (2015) Agonists for nuclear receptor Nurr1 enhance its dual functions and improve behavioral deficits in animal models of Parkinson’s disease. P.N.A.S. 112(28):8756-61. PMID: 26124091.


Researchers

  • Kwang-Soo Kim, PhD

    Belmont, MA United States


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