Druggability Evaluation of the Neuron Derived Orphan Receptor (NOR-1) Reveals Inverse NOR-1 Agonists

  • The neuron derived orphan receptor (NOR-1, NR4A3) is among the least studied nuclear receptors. Its physiological role and therapeutic potential remain widely elusive which is in part due to the lack of chemical tools that can directly modulate NOR-1 activity. To probe the possibility of pharmacological NOR-1 modulation, we have tested a drug fragment library for NOR-1 activation and repression. Despite low hit-rate (<1 %), we have obtained three NOR-1 ligand chemotypes one of which could be rapidly expanded to an analogue comprising low micromolar inverse NOR-1 agonist potency and altering NOR-1 regulated gene expression in a cellular setting. It confirms druggability of the transcription factor and may serve as an early tool to assess the role and potential of NOR-1.

Download full text files

Export metadata

Metadaten
Author:Daniel Zaienne, Silvia ArifiGND, Julian MarschnerORCiDGND, Jan Peter HeeringORCiDGND, Daniel MerkORCiDGND
URN:urn:nbn:de:hebis:30:3-735252
DOI:https://doi.org/10.1002/cmdc.202200259
ISSN:1860-7187
Parent Title (English):ChemMedChem
Publisher:Wiley-VCH
Place of publication:Weinheim
Document Type:Article
Language:English
Date of Publication (online):2022/06/15
Date of first Publication:2022/06/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/04/14
Tag:NR4A3; fragment screening; neurodegeneration; nuclear receptor; transcription factor
Volume:17
Issue:16, art. e202200259
Article Number:e202200259
Page Number:5
First Page:1
Last Page:5
Note:
This research was financially supported by the Aventis Foundation (Life Science Bridge Award to D.M.). This project received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under Grant Agreement No. 875510. The JU received support from the European Union's Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for the Advancement of Learning McGill University, Kungliga Tekniska Hoegskolan, Diamond Light Source Limited. Gal4-VP16 was a gift from Lea Sistonen (Addgene plasmid #71728). Open Access funding enabled and organized by Projekt DEAL.
HeBIS-PPN:508625556
Institutes:Biochemie, Chemie und Pharmazie
Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International

OPUS4 Logo