SAT-250 - High-Throughput Drug Screening Identifies Molecular Signaling Pathways That Dissociate Glucocorticoid Receptor Signaling

Synthetic glucocorticoids like dexamethasone (DEX) are widely used for the treatment of inflammatory diseases like rheumatoid arthritis and inflammatory bowel diseases. Glucocorticoids indeed are highly effective anti-inflammatory drugs, but prolonged exposure oftentimes results in metabolic, musculoskeletal and neurocognitive adverse effects. The identification of molecular signaling pathways that have the potential to skew glucocorticoid signaling from pathways that underlie adverse effect towards anti-inflammatory activity may therefore be highly valuable to improve the therapeutic index.
In this study we performed a high-throughput drug library screening with 2919 FDA-approved compounds to identify molecular pathways that dissociate GR signaling. This drug screening was performed at a dose of 1 µM using three complementary reporter cell lines to simultaneously probe GR transactivation (A549-GRE_Luc), inflammatory signaling (A549-NFkB-Luc) and toxicity (A549-Neo_Luc). We aimed to identify non-toxic drugs that affect GR signaling in a dissociated manner as defined by decreasing DEX-induced GR transactivation while preserving GR-mediated transrepression of TNFα-induced NFkB activity.
From our drug screening we identified 85 non-toxic drugs that attenuated DEX-induced GR transactivation by over 25%. Of these 53 compounds preserved the anti-inflammatory effects of DEX on NFkB activity. We excluded several known chemotherapeutics and performed titration experiments with the remaining 46 drugs. We identified six drugs that exhibited GR dissociating properties at low doses ( < 30 nM), including two drugs respectively involved in the subcellular GR localization and intracellular glucocorticoid levels. The other four drugs target other nuclear receptor subtypes that potentially interact directly with the GR. We confirmed dissociative GR signaling upon co-treatment with a drug involved in nucleocytoplasmic GR shuttling. This drug attenuated DEX-induced expression of GR-responsive genes FKBP5 and GILZ and prevented homologous GR downregulation, while suppression of the inflammatory gene CCL2 by DEX was preserved.
In conclusion, we identified 6 FDA-approved drugs with distinct molecular targets that dissociate GR signaling, thereby potentially improving the therapeutic index.

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