Discovery of selective glucocorticoid receptor modulators by multiplexed reporter screening

Anthony N. Gerber, Kiriko Masuno, Marc I. Diamond

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4929-4934
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number12
DOIs
StatePublished - Mar 24 2009

Keywords

  • Combinatorial therapy
  • Fluorescent protein
  • High-throughput screen
  • Inhibitor selective modulator

ASJC Scopus subject areas

  • General

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