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Título: Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators
Autor(es): Arnold, Leggy A.
Estébanez-Perpiñá, Eva
Togashi, Marie
Jouravel, Natalia
Shelat, Anang
McReynolds, Andrea C.
Mar, Ellena
Nguyen, Phuong
Baxter, John Darling
Fletterick, Robert J.
Webb, Paul
Guy, Rodney Kiplin
Assunto: Moléculas
Proteínas
Tireóide - hormônios
Data de publicação: Dez-2005
Editora: The American Society for Biochemistry and Molecular Biology, Inc.
Referência: ARNOLD, Leggy A. et al. Discovery of small molecule inhibitors of the interaction of the thyroid hormone receptor with transcriptional coregulators. The Journal of Biological Chemistry, v. 280, n. 52, p. 43048-43055, dez. 2005. Disponível em: <http://www.jbc.org/content/280/52/43048.full?sid=e5b2453f-2040-4078-b46d-67ae4676ed92>. Acesso em: 29 maio 2013.
Resumo: 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.
Licença: The Journal of Biological Chemistry - Authors need NOT contact the journal to obtain rights to reuse their own material. They are automatically granted permission to do the following: Reproduce an article for use in the author's courses. (If the author is employed by an academic institution, that institution also may reproduce the article for teaching purposes.). Fonte: http://www.jbc.org/site/misc/Copyright_Permission.xhtml. Acesso em: 20 maio 2013.
DOI: https://dx.doi.org/10.1074/jbc.M506693200
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