1. Academic Validation
  2. Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing

Development of Nurr1 agonists from amodiaquine by scaffold hopping and fragment growing

  • Commun Chem. 2024 Jun 29;7(1):149. doi: 10.1038/s42004-024-01224-0.
Minh Sai 1 Emily C Hank 1 Hin-Man Tai 2 Till Kasch 1 Max Lewandowski 1 Michelle Vincendeau 2 3 Julian A Marschner 1 Daniel Merk 4
Affiliations

Affiliations

  • 1 Ludwig-Maximilians-Universität München, Department of Pharmacy, 81377, Munich, Germany.
  • 2 Helmholtz Munich, Institute of Virology, 85764, Munich, Germany.
  • 3 Technical University of Munich, Institute of Virology, School of Medicine, 81675, Munich, Germany.
  • 4 Ludwig-Maximilians-Universität München, Department of Pharmacy, 81377, Munich, Germany. daniel.merk@cup.lmu.de.
Abstract

The neuroprotective transcription factor nuclear receptor-related 1 (Nurr1) has shown great promise as a therapeutic target in Parkinson's and Alzheimer's disease as well as multiple sclerosis but high-quality chemical tools for pharmacological target validation of Nurr1 are rare. We have employed the weak Nurr1 modulator amodiaquine (AQ) and AQ-derived fragments as templates to design a new Nurr1 agonist chemotype by scaffold hopping and fragment growing strategies. Systematic structural optimization of this scaffold yielded Nurr1 agonists with nanomolar potency and binding affinity. Comprehensive in vitro profiling revealed efficient cellular target engagement and compliance with the highest probe criteria. In human midbrain organoids bearing a Parkinson-driving LRRK2 mutation, a novel Nurr1 agonist rescued tyrosine hydroxylase expression highlighting the potential of the new Nurr1 modulator chemotype as lead and as a chemical tool for biological studies.

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