title: Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening.
abstract: Glucocorticoids are widely used to suppress inflammation and treat various immune-mediated diseases. Some glucocorticoid receptor (GR)-regulated genes mediate the therapeutic response, whereas others cause debilitating side effects. To discover selective modulators of the GR response, we developed a high-throughput, multiplexed system to monitor regulation of 4 promoters simultaneously. An initial screen of 1,040 natural products and Food and Drug Administration-approved drugs identified modulators that caused GR to regulate only a subset of its target promoters. Some compounds selectively inhibited GR-mediated gene activation without altering the repression of cytokine expression by GR. This approach will facilitate identification of genes and small molecules that augment beneficial effects of GR and diminish deleterious ones. Our results have important implications for the development of GR modulators and the identification of cross-talk pathways that control selective GR gene regulation.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA 94143-2280, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Gerber
authors.forename: Kiriko
authors.initials: K
authors.lastname: Masuno
authors.forename: Marc I
authors.initials: MI
authors.lastname: Diamond
mesh_terms: D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001681:Biological Assay; D002208:Caproates / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D005456:Fluorescent Dyes / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D051379:Mice; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012394:Rosaniline Dyes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014052:Toluidines / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D018943:Anthracyclines; D002208:Caproates; D016207:Cytokines; D005456:Fluorescent Dyes; D008024:Ligands; D011965:Receptors, Glucocorticoid; D012394:Rosaniline Dyes; D014052:Toluidines; C005409:pararosaniline; D001312:Aurintricarboxylic Acid; C017037:aurin