Exploring Fatty Acid Mimetics as NR4A Ligands

The ligand-activated
transcription factors Nur77, Nurr1, and NOR-1
forming the NR4A family of nuclear receptors are considered as potential
targets in various pathologies, including neurodegeneration and cancer.
However, chemical tools for pharmacological NR4A modulation as a prerequisite
for target validation are rare. Recent findings suggest that NR4As
bind fatty acid metabolites and fatty acid mimetic (FAM) drugs, opening
new opportunities for NR4A modulator development. We have explored
the chemical space of FAM NR4A ligands by using fragment screening,
in silico analysis, and systematic structure–activity relationship
evaluation. From a chemically diverse library of 92 fragments, we
identified 11 new FAM NR4A agonist and inverse agonist scaffolds.
Structural optimization of the most active FAM fragment yielded NR4A
agonists with submicromolar potency and binding affinity, demonstrating
remarkable potential of FAM as NR4A-modulating tools and drugs.