Nurr1 (NR4A2) activators

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Chang-Hwan Kim, Kwang-Soo Kim (senior author), Gregory Petsko and colleagues (2015 screen; the paper lists 20 authors); Kwang-Soo Kim's group at McLean Hospital / Harvard made the 2023 optimised compound. HanAll Biopharma, Daewoong Pharmaceutical and NurrOn Pharmaceuticals developed HL192 (also called ATH-399A); the Michael J. Fox Foundation gave NurrOn a $1.7 million grant for the Phase 1 (per the companies' release as reported by NeurologyLive).

What happened

Nurr1 is a transcription factor (a protein that switches other genes on or off). It is needed to build dopamine neurons and keep them alive in adults, and its levels are reported to fall in ageing and sporadic Parkinson's brains. It also seems to restrain inflammation-driven neuron death.

• 2015. A screen found three compounds sharing one chemical scaffold (4-amino-7-chloroquinoline) that boost Nurr1 activity: the antimalarials amodiaquine and chloroquine, and glafenine. Amodiaquine and chloroquine bind Nurr1's ligand-binding domain, raised the activity of dopamine-neuron genes, dampened inflammatory genes in microglia (the brain's immune cells), and improved behaviour in the 6-hydroxydopamine rat model without dyskinesia (involuntary movements) (Kim et al., PNAS 2015;112:8756–8761, DOI 10.1073/pnas.1509742112). This is a toxin model that does not mimic the slow human disease.
• 2023. The same group made over 570 variants of the shared 4-amino-7-chloroquinoline structure. The best, 4A7C-301, enters the brain, protected dopamine neurons in the MPTP mouse model and improved motor and smell deficits in a synuclein mouse model, and did not block autophagy (cell recycling) the way chloroquine does (Nat Commun 2023;14:4283).
• 2023–24. A different, company-made Nurr1 activator, HL192, started first-in-human dosing in October 2023 (ClinicalTrials.gov NCT06088784, healthy volunteers, completed April 2024, 76 participants). It met its safety and tolerability goals, with adverse events similar to placebo and all doses well below the no-effect level (announced 25 Nov 2024). The companies plan a Parkinson's patient trial; no such trial is on ClinicalTrials.gov under HL192 or ATH-399A (searched 20 Oct 2026).

Why it moved us toward a cure

Nurr1 was already known to be essential for dopamine neurons (landmark 176). It points at a different kind of target: not clumped protein or one gene, but the cell's own maintenance programme. It sits in the vulnerability lane because it concerns what keeps dopamine neurons alive, and carries a growth-factors tag because Nurr1 works alongside GDNF-type signalling and the aim is to protect rather than replace neurons (see the growth-factor trials, landmark 146). It is an alternative route to the same goal, without surgery.

Outcome

Open and preclinical. No Parkinson's trial is registered. Mouse results have repeatedly failed to carry over, and chloroquine-type compounds have off-target concerns.

Sources

• Kim CH et al., PNAS 2015;112:8756–8761, DOI 10.1073/pnas.1509742112, PMID 26124091 (abstract read via Europe PMC) · Pharmaceutical Journal report
• Kim W et al., "An optimized Nurr1 agonist provides disease-modifying effects in Parkinson's disease models", Nat Commun 2023;14:4283, DOI 10.1038/s41467-023-39970-9
• HL192 first-in-human start, NeurologyLive Oct 2023 · HL192 phase 1 completion, 26 Nov 2024 · ClinicalTrials.gov NCT06088784
• No correction or retraction found for the two papers (Crossref and Europe PMC, 20 Oct 2026).
• Not yet verified: the size of the 2015 drug screen and the claim that 4A7C-301 spares autophagy, unlike chloroquine (neither is in the abstracts); the 2015 authors' affiliations; whether Nurr1 levels fall in ageing and sporadic Parkinson's brains (stated as reported, not checked); any HL192 patient trial.