Chemogenomics for NR1 nuclear hormone receptors

• Published in: Nature communications Vol. 15; no. 1; pp. 5201 - 13
• Main Authors: Isigkeit, Laura, Schallmayer, Espen, Busch, Romy, Brunello, Lorene, Menge, Amelie, Elson, Lewis, Müller, Susanne, Knapp, Stefan, Stolz, Alexandra, Marschner, Julian A., Merk, Daniel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-06-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/47; 631/154/1435/2417; 631/154/555; 631/92/612/388; 96/98; Animals; Antagonists; Autophagy; Autophagy - drug effects; Autophagy - genetics; Binding; Cell death; Cell Line, Tumor; Chemical activity; Chemogenomics; Gene expression; Genomics - methods; Glutamic acid receptors; HEK293 Cells; Hormones; Humanities and Social Sciences; Humans; Inflammation; Inverse agonists; Ligands; Lipids; Metabolites; Mice; multidisciplinary; N-Methyl-D-aspartic acid receptors; Nuclear receptors; Receptors; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Science; Science (multidisciplinary); Target recognition; Therapeutic targets; Toxicity; Transcription factors; Vitamins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49493-6

Nuclear receptors (NRs) regulate transcription in response to ligand binding and NR modulation allows pharmacological control of gene expression. Although some NRs are relevant as drug targets, the NR1 family, which comprises 19 NRs binding to hormones, vitamins, and lipid metabolites, has only been partially explored from a translational perspective. To enable systematic target identification and validation for this protein family in phenotypic settings, we present an NR1 chemogenomic (CG) compound set optimized for complementary activity/selectivity profiles and chemical diversity. Based on broad profiling of candidates for specificity, toxicity, and off-target liabilities, sixty-nine comprehensively annotated NR1 agonists, antagonists and inverse agonists covering all members of the NR1 family and meeting potency and selectivity standards are included in the final NR1 CG set. Proof-of-concept application of this set reveals effects of NR1 members in autophagy, neuroinflammation and cancer cell death, and confirms the suitability of the set for target identification and validation.
In this work, the authors compile a chemogenomics library for NR1 nuclear hormone receptors to advance studies on unexplored therapeutic potential of these transcription factors. Its application in phenotypic settings revealed NR1 involvement in autophagy.