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.