An optimized Nurr1 agonist provides disease-modifying effects in Parkinson’s disease models

Woori Kim, Mohit Tripathi, Chunhyung Kim, Satyapavan Vardhineni, Young Cha, Shamseer Kulangara Kandi, Melissa Feitosa, Rohit Kholiya, Eric Sah, Anuj Thakur, Yehan Kim, Sanghyeok Ko, Kaiya Bhatia, Sunny Manohar, Young-Bin Kong, Gagandeep Sindhu, Yoon-Seong Kim, Bruce Cohen, Diwan S. Rawat () and Kwang-Soo Kim ()
Additional contact information
Woori Kim: McLean Hospital, Harvard Medical School
Mohit Tripathi: University of Delhi
Chunhyung Kim: McLean Hospital, Harvard Medical School
Satyapavan Vardhineni: University of Delhi
Young Cha: McLean Hospital, Harvard Medical School
Shamseer Kulangara Kandi: University of Delhi
Melissa Feitosa: McLean Hospital, Harvard Medical School
Rohit Kholiya: University of Delhi
Eric Sah: McLean Hospital, Harvard Medical School
Anuj Thakur: University of Delhi
Yehan Kim: McLean Hospital, Harvard Medical School
Sanghyeok Ko: McLean Hospital, Harvard Medical School
Kaiya Bhatia: McLean Hospital, Harvard Medical School
Sunny Manohar: University of Delhi
Young-Bin Kong: McLean Hospital, Harvard Medical School
Gagandeep Sindhu: University of Delhi
Yoon-Seong Kim: Rutgers University
Bruce Cohen: McLean Hospital, Harvard Medical School
Diwan S. Rawat: University of Delhi
Kwang-Soo Kim: McLean Hospital, Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson’s disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1’s transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD.

Date: 2023
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DOI: 10.1038/s41467-023-39970-9

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