Chemogenomics for NR1 nuclear hormone receptors

Laura Isigkeit, Espen Schallmayer, Romy Busch, Lorene Brunello, Amelie Menge, Lewis Elson, Susanne Müller, Stefan Knapp, Alexandra Stolz, Julian A. Marschner and Daniel Merk ()
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Laura Isigkeit: Institute of Pharmaceutical Chemistry
Espen Schallmayer: Institute of Pharmaceutical Chemistry
Romy Busch: Department of Pharmacy
Lorene Brunello: Institute of Pharmaceutical Chemistry
Amelie Menge: Institute of Pharmaceutical Chemistry
Lewis Elson: Institute of Pharmaceutical Chemistry
Susanne Müller: Institute of Pharmaceutical Chemistry
Stefan Knapp: Institute of Pharmaceutical Chemistry
Alexandra Stolz: Goethe University Frankfurt
Julian A. Marschner: Department of Pharmacy
Daniel Merk: Institute of Pharmaceutical Chemistry

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49493-6

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