A quantitative high-throughput screen identifies novel inhibitors of the interaction of thyroid receptor β with a peptide of steroid receptor coactivator 2

Ronald L. Johnson, Jong Yeon Hwang, Leggy A. Arnold, Ruili Huang, Jennifer Wichterman, Indre Augustinaite, Christopher P. Austin, James Inglese, R. Kiplin Guy, Wenwei Huang

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The thyroid hormone receptors (TR) are members of the nuclear hormone receptor (NHR) superfamily that regulate development, growth, and metabolism. Upon ligand binding, TR releases bound corepressors and recruits coactivators to modulate target gene expression. Steroid receptor coactivator 2 (SRC2) is an important coregulator that interacts with TRβ to activate gene transcription. To identify novel inhibitors of the TRβ and SRC2 interaction, the authors performed a quantitative high-throughput screen (qHTS) of a TRβ-SRC2 fluorescence polarization assay against more than 290 000 small molecules. The qHTS assayed compounds at 6 concentrations up to 92 μM to generate titration-response curves and determine the potency and efficacy of all compounds. The qHTS data set enabled the characterization of actives for structure-activity relationships as well as for potential artifacts such as fluorescence interference. Selected qHTS actives were tested in the screening assay using fluoroprobes labeled with Texas Red or fluorescein. The retest identified 19 series and 4 singletons as active in both assays with 40% or greater efficacy, free of compound interference, and not toxic to mammalian cells. Selected compounds were tested as independent samples, and a methylsulfonylnitrobenzoate series inhibited the TRβ-SRC2 interaction with 5 μM IC50. This series represents a new class of thyroid hormone receptor-coactivator modulators.

Original languageEnglish
Pages (from-to)618-627
Number of pages10
JournalJournal of Biomolecular Screening
Volume16
Issue number6
DOIs
StatePublished - Jul 2011

Keywords

  • HTS
  • coactivator
  • protein-protein interaction
  • small molecule
  • thyroid receptor

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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