Chemogenomics for NR1 nuclear hormone receptors

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.


Statistics
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Data analysis
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Life sciences
Behavioural & social sciences Ecological, evolutionary & environmental sciences For a reference copy of the document with all sections, see nature.com/documents/nr-reporting-summary-flat.pdf

Life sciences study design
All studies must disclose on these points even when the disclosure is negative.A priori power calculation assuming a power of 0.8, significance level 0.05, and aiming to detect large effect sizes with ANOVA (i.e.f=0.4 according to Cohen 1982) within 72 groups (CG set + controls) supports a group size of 3-4 biological replicates for CG set application.Three biological replicates were considered sufficient and economic for individual compound characterization (on-target activity, selectivity, etc.) since all compounds had been described and characterized before and were meant to be comparatively profiled and validated for CG set inclusion in this study.

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All in vitro biological experiments have been successfully replicated in biologically independent repeats.
Not relevant in this study.Only in vitro assays were conducted in which samples are derived from the same clone and in which the entire CG set was applied.Nevertheless, different repeats were conducted on different dates and from different harvests/transfections/seeds to account for covariates introduced by the experimental procedures.
Investigators were blinded in experiments in which the complete CG library was applied/used as a set.Additionally, the biological proof-ofconcept applications of the CG set were purely descriptive and not intended to provide evidence for an a priori hypothesis.Blinding was not meaningful in experiments referring to analytical characterization, quality control and selectivity profiling.
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