Drug fragment screening identified new Nur77 modulators with reduced lipophilicity compared to known ligands.
•An identified N-Phenylpiperazine scaffold could be tuned to Nur77 agonism and inverse agonism.
•Molecular docking and competition experiments suggested binding of N-phenylpiperazines to the THPN binding site.
•Virtual screening of N-phenylpiperazines as fragment extension strategy yielded Nur77 agonists with increased potency.
•A Nur77 agonist discovered by virtual screening exhibited preference over the related receptors Nurr1 and NOR-1.
AbstractThe transcription factor nerve growth factor-induced clone B (NGFI-B, Nur77, NR4A1) is an orphan nuclear receptor playing a role in cell survival and apoptosis regulation. Pharmacological Nur77 modulation holds promise for cancer and (neuro-)inflammatory disease treatment. The available Nur77 ligand scaffolds based on highly lipophilic natural products cytosporone B, celastrol and isoalantolactone are inadequate for the development of potent Nur77 modulators with favorable properties as chemical tools and future drugs. By fragment library screening and subsequent modeling for fragment extension, we have obtained a set of new Nur77 ligands offering alternative chemotypes for the development of Nur77 agonists and inverse agonists. Computer-aided fragment extension in a second stage screening yielded a Nur77 agonist with significant activation efficacy and preference over the related NR4A receptors.
KeywordsTranscription factor
NR4A
Cancer
Neurodegeneration
Virtual screening
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