18th September 2020

Chemical tools reveal mechanistic insights

Last year’s Award Winner Daniel Merk and his team at Goethe University discovered three non-steroidal anti-inflammatory drugs (NSAIDs) as first known inverse Nurr1 agonists.

The ligand-sensing transcription factor Nurr1 is ascribed high potential as molecular target for Parkinson’s Disease and Alzheimer’s Disease treatment. However, synthetic ligands to study the receptors cellular role and molecular mechanisms are lacking. Inspired by a PDB-deposited X-ray structure of Nurr1 in complex with the arachidonic acid metabolite prostaglandin A1, a team at the Institute of Pharmaceutical Chemistry of Goethe University Frankfurt discovered three non-steroidal anti-inflammatory drugs (NSAIDs) as first known inverse Nurr1 agonists. Together with the previously reported Nurr1 agonists amodiaquine and chloroquine, these molecules add up to an initial set of chemical tool compounds to decipher the molecular and cellular function of Nurr1.

In mechanistic studies, this set of chemical tools demonstrated enhanced recruitment of four co-regulator interaction motifs to Nurr1 by agonists and their displacement upon inverse agonist binding. Additionally, the monomer-dimer equilibrium was markedly affected in an oppositional manner by the Nurr1 agonists and inverse agonists pointing to altered dimerization and co-regulator interactions as major regulatory contributions to Nurr1 modulation. Together with the existence of different human DNA response elements for the Nurr1 monomer, homodimer and RXR-heterodimer, this finding suggests potentially an opportunity to control Nurr1 function in a gene-selective fashion.

The first inverse Nurr1 agonists valuably expand the scarce collection of Nurr1 modulators both as chemical tools and as leads for medicinal chemistry. In addition to preliminary mechanistic insights in molecular Nurr1 regulation, the initial set of tools may help further elucidating the biology of Nurr1 and validating this orphan as target in neurodegenerative diseases.

The full article can be found at: https://www.nature.com/articles/s42004-020-0331-0

The authors around Daniel Merk are grateful to the Aventis Foundation and the Life Sciences Bridge Award which has importantly contributed to the success of this project.