NR4A receptors (NR4A1–3) are orphan nuclear receptors sharing ~66–69% sequence identity and functioning as transcription factors through monomeric, homodimeric, or RXR-heterodimeric forms. They regulate gene expression via response elements such as NBRE, NurRE, and DR5. Among them, NR4A2 (Nurr1) is highly expressed in the central nervous system and is associated with neuroprotective and anti-neuroinflammatory effects, with relevance to neurodegenerative diseases including Parkinson’s, Alzheimer’s, and multiple sclerosis.

Chemical structures of JV332 and the negative control JV339.

JV332 (compound 53) is a potent NR4A agonist derived from optimization of vidofludimus-based scaffolds. It demonstrates strong agonistic activity across NR4A receptors and promotes neuroprotective gene expression. A structurally related inactive compound (JV339, compound 54) serves as a negative control.

Biological activity summary:

• Binding affinity (ITC): Kd 0.10 ± 0.1 μM to recombinant Nurr77
• Cellular potency was determined in Gal4-NR4A hybrid reporter assays yielding the following data: EC₅₀ (Nurr1): 0.092 ± 0.008 μM, EC₅₀ (Nurr77): 0.098 ± 0.007 μM, EC₅₀ (Nor-1): 0.09 ± 0.02 μM, EC₅₀ (NBRE): 94 nM, EC₅₀ (NurRE): 99 nM, EC₅₀ (DR5): 98 nM.
• Maximum activation: ~ 4-fold over base line (near full agonist) 
• Low cytotoxicity (>10 µM in HEK293 cells)
• JV332 is selective over nuclear receptors outside the NR4A family with moderate DHODH activation at 3 μM (EC50 = 4.3 ± 0.4 μM).