The orphan nuclear receptor Nurr1 is responsive to non-steroidal anti-inflammatory drugs

  • 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.

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Author:Sabine Willems, Whitney KiluGND, Xiaomin NiORCiDGND, Apirat ChaikuadORCiD, Stefan KnappORCiD, Jan Peter HeeringORCiDGND, Daniel MerkORCiDGND
URN:urn:nbn:de:hebis:30:3-555086
DOI:https://doi.org/10.1038/s42004-020-0331-0
ISSN:2399-3669
Parent Title (English):Communications chemistry
Publisher:Macmillan Publishers Limited, part of Springer Nature
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2020/07/03
Date of first Publication:2020/07/03
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2020/09/10
Tag:Chemical tools; Drug screening; Medicinal chemistry
Volume:3
Issue:art. 85
Page Number:12
First Page:1
Last Page:12
Note:
This article is licensed under a Creative Commons Attribution 4.0 International License http://creativecommons.org/licenses/by/4.0/.
HeBIS-PPN:47097012X
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universit├Ątspublikationen
Open-Access-Publikationsfonds:Biochemie, Chemie und Pharmazie
Licence (German):License LogoCreative Commons - Namensnennung 4.0