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Papers In Press, published online ahead of print October 31, 2005
Chemical Biology and Therapeutics, St Jude Children's Research Hosptial, Memphis, TN 38105
Corresponding Author: kip.guy{at}stjude.org
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. TRs’ binding 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 ß-aminoketones, which exhibited IC50 values of around 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 approximately 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.
J. Biol. Chem, 10.1074/jbc.M506693200
Submitted on June 20, 2005
Revised on October 18, 2005
Accepted on October 31, 2005
Discovery of small molecule inhibitors of the interaction of thyroid hormone receptor with transcriptional coregulators
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