research8(1) - Mutant-Selective Thyromimetics for the...

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Unformatted text preview: Mutant-Selective Thyromimetics for the Chemical Rescue of Thyroid Hormone Receptor Mutants Associated with Resistance to Thyroid Hormone Youheng Shi, Haifen Ye, Kristian H. Link, Marc C. Putnam, Isaac Hubner, Sarah Dowdell, and John T. Koh* Department of Chemistry and Biochemistry, Uni V ersity of Delaware, Newark, Delaware 19716 Recei V ed August 16, 2004; Re V ised Manuscript Recei V ed January 12, 2005 ABSTRACT : The thyroid hormone receptors (TRs) are ligand-dependent transcription factors that control the expression of multiple genes involved in development and homeostasis in response to thyroid hormone (triiodothyronine, T3). Mutations to TR that reduce or abolish ligand-dependent transactivation function are associated with resistance to thyroid hormone (RTH), an autosomal dominant human genetic disease. A series of neutral alcohol-based compounds, based on the halogen-free thyromimetic GC-1, have been designed, synthesized, and evaluated in cell-based assays for their ability to selectively rescue three of the most common RTH-associated mutations (i.e., Arg320 f Cys, Arg320 f His, and Arg316 f His) that affect the basic carboxylate-binding arginine cluster of TR . Several analogues show improved potency and activity in the mutant receptors relative to the parent compound GC-1. Most significantly, two of these mutant-complementing thyromimics show high potency and activity with a strong preference for the mutant receptors over wild-type TR R (wt), that is associated with the cardiotoxic actions of T3. The compounds were evaluated in reporter gene assays using the four common thyroid hormone response elements, DR4, PAL, F2 (LAP), and TSH, and show activities and selectivites consistent with their unique potential as agents to selectively rescue thyroid function to these RTH-associated mutants. Thyroid hormone action is mediated by thyroid hormone receptors (TRs), 1 which belong to the superfamily of nuclear/ steroid hormone receptors ( 1- 4 ). Thyroid hormone receptors function as ligand-dependent transcriptional regulators that control the expression of a specific set of genes involved in development and homeostasis in response to triiodothyronine (T3). Thyroid hormone affects brain development, skeletal maturation, thermogenesis, heart contractility, and the secre- tion and metabolic turnover of different hormones ( 5 , 6 ). TRs bind as homo- or heterodimers to DNA at specific hormone response elements (HREs) found in the promoters of hormone responsive genes. There are two subtypes of the thyroid hormone receptors, TR R and TR . Each subtype is expressed in at least two isoforms, TR R 1, TR R 2, TR 1, and TR 2. The isoforms TR R 1, TR 1, and TR 2 bind thyroid hormone and act as ligand-regulated transcription factors....
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This note was uploaded on 12/04/2011 for the course CHEM 590A taught by Professor Staff during the Summer '10 term at University of Illinois, Urbana Champaign.

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research8(1) - Mutant-Selective Thyromimetics for the...

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