Abstract
The nine human NR3 nuclear receptors translate steroid hormone signals in transcriptomic responses and operate multiple highly important processes ranging from development over reproductive tissue function to inflammatory and metabolic homeostasis. Although several NR3 ligands such as glucocorticoids are invaluable drugs, this family is only partially explored, for example, in autoimmune diseases and neurodegeneration, but may hold therapeutic potential in new areas. Here we report a chemogenomics (CG) library to reveal elusive effects of NR3 receptor modulation in phenotypic settings. 34 highly annotated and chemically diverse ligands covering all NR3 receptors were selected considering complementary modes of action and activity, selectivity and lack of toxicity. Endoplasmic reticulum stress resolving effects of N3 CG subsets in proof-of-concept application validate suitability of the set to connect phenotypic outcomes with targets and to explore NR3 receptors from a translational perspective.