Precision Nurr1 Modulators for Parkinson’s Disease

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SyNoesis is advancing selective modulators of the Nurr1:RXRα complex toward IND, with a clear 24-month development path and biomarker-enabled clinical strategy.

• No disease-modifying therapy currently exists.
• Progressive loss of dopaminergic neurons drives irreversible disability.
• Current treatments are symptomatic and decline in efficacy over time.
• Neurodegeneration is multi-pathway: protein aggregation, inflammation, neuronal death.

Parkinson’s disease represents a multi-billion-euro market opportunity with strong regulatory support for innovative mechanisms.

Nurr1 (NR4A2) is a master transcriptional regulator essential for dopaminergic neuron differentiation, survival, and functional maintenance.

Multiple lines of evidence link Nurr1 to Parkinson’s disease:

• Reduced expression in sporadic PD midbrain tissue
• Reduced expression associated with genetic mutations in familial PD
• Functional impairment contributing to neuroinflammatory and proteostatic dysregulation

Targeted modulation of Nurr1 offers a disease-modifying strategy that addresses the molecular drivers of dopaminergic vulnerability and neuroinflammation simultaneously.

SyNoesis has developed selective modulators of the Nurr1:RXRα complex that:

• Are unique selective biophysical allosteric activators of Nurr1 through targeting Nurr1:RXRα by binding to RXRα
• Activate several neuroprotective trophic pathways
• Suppress neuroinflammation
• Enhance proteostasis and protein clearance

Unlike classical RXR agonists, our compounds produce a distinct conformational and transcriptional outcome, validated through orthogonal biophysical methods and externally confirmed.

✔ Direct activity in human dopaminergic neurons derived from Parkinson’s patients
✔ Therapeutic efficacy in advanced pathology mouse models (not prophylactic)
✔ Reduction of α-synuclein pathology
✔ Anti-inflammatory microglial modulation
✔ Biomarkers of in vivo efficacy confirmed

Our compounds reverse core mechanisms of neurodegeneration in both neuronal and inflammatory compartments.

• 4 generations of medicinal chemistry optimization
• 7 advanced candidates across 4 scaffolds
• Brain penetration confirmed
• Improved metabolic stability
• No early hERG liabilities
• 2+2 PCT patent families fully owned

Clinical candidates:
Lead series: SNT-137 / SNT-154
Backup: Gen4 series

• First-in-class Nurr1 mechanism

A unique biophysical MOA vs competitor Nurr1:RXRα modulators
• Multi-pathway disease-modifying potential
• Human neuron validation
• Strong IP position
• IND-ready in 24 months
• Experienced translational leadership
• External validation and biotech awards