Comparative Profiling and Chemogenomics Application of Chemical Tools for NR4A Nuclear Receptors

The ligand-activated transcription factors of the NR4A
family are
implicated as promising drug targets with neuroprotective and anticancer
potential and attract strong attention in drug discovery. Several
NR4A modulators have been described, but a validated set of direct
ligands for biological studies is lacking. Here, we profiled the reported
and commercially available agonists and inverse agonists under uniform
conditions in several orthogonal test systems to establish a highly
annotated tool and gain comprehensive insights into the NR4A modulator
characteristics. This comparative profiling revealed a lack of on-target
binding and modulation for several putative NR4A ligands and validated
a set of chemically diverse compounds as direct NR4A modulators for
chemogenomics-based target identification studies. Prospective applications
unveiled roles of NR4A receptors in endoplasmic reticulum stress and
adipocyte differentiation, demonstrating suitability of the set to
link the orphan targets with phenotypic effects.