The orphan nuclear receptor Nurr1 is responsive to non-steroidal anti-inflammatory drugs.
Journal
Communications chemistry
ISSN: 2399-3669
Titre abrégé: Commun Chem
Pays: England
ID NLM: 101725670
Informations de publication
Date de publication:
03 Jul 2020
03 Jul 2020
Historique:
received:
24
12
2019
accepted:
05
06
2020
entrez:
27
1
2023
pubmed:
3
7
2020
medline:
3
7
2020
Statut:
epublish
Résumé
Nuclear receptor related 1 (Nurr1) is an orphan ligand-activated transcription factor and considered as neuroprotective transcriptional regulator with great potential as therapeutic target for neurodegenerative diseases. However, the collection of available Nurr1 modulators and mechanistic understanding of Nurr1 are limited. Here, we report the discovery of several structurally diverse non-steroidal anti-inflammatory drugs as inverse Nurr1 agonists demonstrating that Nurr1 activity can be regulated bidirectionally. As chemical tools, these ligands enable unraveling the co-regulatory network of Nurr1 and the mode of action distinguishing agonists from inverse agonists. In addition to its ability to dimerize, we observe an ability of Nurr1 to recruit several canonical nuclear receptor co-regulators in a ligand-dependent fashion. Distinct dimerization states and co-regulator interaction patterns arise as discriminating factors of Nurr1 agonists and inverse agonists. Our results contribute a valuable collection of Nurr1 modulators and relevant mechanistic insights for future Nurr1 target validation and drug discovery.
Identifiants
pubmed: 36703399
doi: 10.1038/s42004-020-0331-0
pii: 10.1038/s42004-020-0331-0
pmc: PMC9814838
doi:
Types de publication
Journal Article
Langues
eng
Pagination
85Informations de copyright
© 2020. The Author(s).
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