Methylsulfonylnitrobenzoates, a new class of irreversible inhibitors of the interaction of the thyroid hormone receptor and its obligate coactivators that functionally antagonizes thyroid hormone

J Biol Chem. 2011 Apr 8;286(14):11895-908. doi: 10.1074/jbc.M110.200436. Epub 2011 Feb 14.


Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TRβ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPARγ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TRβ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TRβ to disrupt SRC2 association.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Methylamines / pharmacology
  • Nitrobenzoates / chemistry
  • Nitrobenzoates / pharmacology*
  • Nuclear Receptor Coactivator 2 / metabolism*
  • Piperidines / pharmacology
  • Protein Binding / drug effects
  • Receptors, Thyroid Hormone / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Structure-Activity Relationship


  • Aniline Compounds
  • Methylamines
  • Nitrobenzoates
  • Nuclear Receptor Coactivator 2
  • Piperidines
  • Receptors, Thyroid Hormone
  • piperidine
  • methylamine
  • aniline