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J. Biol. Chem., Vol. 280, Issue 52, 43048-43055, December 30, 2005

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Discovery of Small Molecule Inhibitors of the Interaction of the Thyroid Hormone Receptor with Transcriptional Coregulators^*

Leggy A. Arnold, Eva Estébanez-Perpiñá1, Marie Togashi¶1, Natalia Jouravel, Anang Shelat, Andrea C. McReynolds, Ellena Mar, Phuong Nguyen¶, John D. Baxter¶, Robert J. Fletterick, Paul Webb¶, and R. Kiplin Guy||2

From the Department of Pharmaceutical Chemistry, ^||Department of Molecular and Cellular Pharmacology, Department of Biochemistry and Biophysics, ^¶Diabetes Center and Department of Medicine, University of California, San Francisco, California 94143

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 -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.

Received for publication, June 20, 2005 , and in revised form, October 18, 2005.

^* This work was supported by the Howard Hughes Medical Institute Research Resources Program Grant 76296-549901, Grants DK58080 and DK61648 from the National Institutes of Health, the Sandler Research Foundation, and a UCSF Prostate Cancer SPORE Research Fellowship. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Chemical Biology in Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105. Tel.: 901-495-5714; Fax: 901-495-5715; E-mail: kip.guy{at}stjude.org.

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