# Selective modulators for the nuclear receptor Nurr1

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $353,281

## Abstract

PROJECT SUMMARY
Nuclear receptors are a superfamily of ligand-regulated transcription factors that play fundamental roles in
human development, homeostasis, and disease. These receptors interact with small molecules, protein
partners, and DNA sequences to regulate the transcription of specific target genes. Developing ligands that
stabilize specific conformational states of the receptor, and thus drive the transcription of specific target genes,
is a prerequisite for developing effective nuclear receptor therapeutics.
The nuclear receptor Nurr1 (NR4A2) is widely recognized as a therapeutic target for Parkinson's disease,
potentially modifying both the symptoms and progression of the disease. Current therapeutics for Parkinson's
disease are symptom-modifying only and lose efficacy as the disease progresses. Although “Nurr1 agonists”
have been reported in both the scientific and patent literature, there is little evidence these ligands directly
activate the receptor. The only published crystal structure of Nurr1 reveals two distinctive features that have
hindered progress developing small molecules targeting this receptor: Nurr1 lacks both the canonical nuclear
receptor ligand binding pocket and the classical binding site for protein partners.
Using an orthogonal drug development strategy called disulfide-trapping, we identified ~50 small molecules
that bind directly to Nurr1 and form covalent adducts with a native cysteine residue in the ligand binding
domain. We also identified an endogenous ligand that forms a reversible covalent adduct with the same
cysteine residue. Co-crystal structures for three of these ligand-receptor complexes show Nurr1 in three
distinctly different conformations. The proposed research will capitalize on these findings to develop chemical
probes for Nurr1 that can be used to unravel the receptor's complex biology. Successful completion of these
aims will define the relationships between individual ligand scaffolds, Nurr1 conformational states, and specific
Nurr1 target genes, thereby providing the foundation for rationally developing new PD therapeutics.
In Aim 1, we will generate covalent ligands for Nurr1, suitable for cellular assays, and use them to identify the
target genes associated with different conformational states of the receptor.
In Aim 2, we will identify functional analogs of the endogenous Nurr1 ligand that will enable cellular studies
probing the receptor's regulation.
In Aim 3, we will identify ligands that stabilize additional conformations of the receptor (e.g. heterodimer with
RXR) and solve co-crystal structures of the resulting Nurr1 complexes.

## Key facts

- **NIH application ID:** 9975246
- **Project number:** 5R01NS108404-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Pamela Michael England
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,281
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975246

## Citation

> US National Institutes of Health, RePORTER application 9975246, Selective modulators for the nuclear receptor Nurr1 (5R01NS108404-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975246. Licensed CC0.

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