Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators

J Biol Chem. 2005 Dec 30;280(52):43048-55. doi: 10.1074/jbc.M506693200. Epub 2005 Oct 31.


Thyroid hormone (3,5,3'-triiodo-L-thyronine, T3) is an endocrine hormone that exerts homeostatic regulation of basal metabolic rate, heart rate and contractility, fat deposition, and other phenomena (1, 2). T3 binds to the thyroid hormone receptors (TRs) and controls their regulation of transcription of target genes. The binding of TRs to thyroid hormone induces a conformational change in TRs that regulates the composition of the transcriptional regulatory complex. Recruitment of the correct coregulators (CoR) is important for successful gene regulation. In principle, inhibition of the TR-CoR interaction can have a direct influence on gene transcription in the presence of thyroid hormones. Herein we report a high throughput screen for small molecules capable of inhibiting TR coactivator interactions. One class of inhibitors identified in this screen was aromatic beta-aminoketones, which exhibited IC50 values of approximately 2 microm. These compounds can undergo a deamination, generating unsaturated ketones capable of reacting with nucleophilic amino acids. Several experiments confirm the hypothesis that these inhibitors are covalently bound to TR. Optimization of these compounds produced leads that inhibited the TR-CoR interaction in vitro with potency of approximately 0.6 microm and thyroid signaling in cellular systems. These are the first small molecules irreversibly inhibiting the coactivator binding of a nuclear receptor and suppressing its transcriptional activity.

Publication types

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

MeSH terms

  • Binding, Competitive
  • Dose-Response Relationship, Drug
  • Genetic Vectors
  • Glutathione Transferase / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Ketones / chemistry
  • Kinetics
  • Models, Chemical
  • Models, Molecular
  • Osteosarcoma / pathology
  • Peptides / chemistry
  • Protein Binding
  • Receptors, Thyroid Hormone / antagonists & inhibitors*
  • Receptors, Thyroid Hormone / chemistry*
  • Signal Transduction
  • Thyroid Hormones / metabolism
  • Time Factors
  • Transcription, Genetic*
  • Transfection
  • Triiodothyronine / metabolism


  • Ketones
  • Peptides
  • Receptors, Thyroid Hormone
  • Thyroid Hormones
  • Triiodothyronine
  • Glutathione Transferase