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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. Human NR3 nuclear receptors translate steroid hormone signals in transcriptomic responses and serve as invaluable drug targets, however, their therapeutic potential remains underexplored. Here, the authors report a chemogenomics library of NR3 ligands to reveal elusive effects of NR3 receptor modulation in phenotypic settings, revealing potential NR3-mediated effects in endoplasmic reticulum stress and providing proof-of-concept for its suitability to correlate phenotypic outcomes with molecular targets. [ABSTRACT FROM AUTHOR]

Nuclear receptor modulation enables pharmacological control of gene expression thus rendering the 48 human nuclear receptors as attractive targets for drug discovery. Several nuclear receptor ligands like glucocorticoids are approved and highly important drugs illustrating the therapeutic potential of nuclear receptor modulation. However, a significant portion of the nuclear receptor family is still poorly explored for new therapeutic opportunities which is due to a lack of potent, selective and well-characterized ligands. Preliminary evidence supports great therapeutic potential of several orphan nuclear receptors in various pathologies underlining the need for high-quality chemical tools to enable target validation. Here, we evaluate the characteristics of available nuclear receptor modulators and the gaps in coverage of the nuclear receptor family with chemical tools. We review successful approaches to nuclear receptor modulator development and highlight the opportunities and challenges in closing the gaps of missing tools for understudied nuclear receptors to open new therapeutic avenues. [ABSTRACT FROM AUTHOR]

Public repositories containing compound-bioactivity data for millions of small molecules offer a valuable resource for chemogenomic compound candidate search. Nonetheless, owning to nonuniform data mining, these databases are often incomplete, thus advocating the combined use of data from several repositories to increase target coverage and data accuracy. Here, we present a workflow to generate custom datasets from public databases for mining chemogenomic compound candidates. The compiled set provides flags for differences in structural and bioactivity data and enables rapid extraction of potent and selective bioactive compounds., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)