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

Leggy A. Arnold, Eva Estebanez-Perpina, Marie Togashi, Natalia Jouravel, Anang Shelat, Andrea C. McReynolds, Ellena Mar, Phuong Nguyen, John D. Baxter, Robert J. Fletterick, Paul Webb, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


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 β-aminoketones, which exhibited IC50 values of ∼2 μM. 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 ∼0.6 μM 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.

Original languageEnglish (US)
Pages (from-to)43048-43055
Number of pages8
JournalJournal of Biological Chemistry
Issue number52
StatePublished - Dec 30 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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