Mutant-selective thyromimetics for the chemical rescue of thyroid hormone receptor mutants associated with resistance to thyroid hormone.
Biochemistry
; 44(12): 4612-26, 2005 Mar 29.
Article
en En
| MEDLINE
| ID: mdl-15779888
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 TRbeta 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 --> Cys, Arg320 --> His, and Arg316 --> His) that affect the basic carboxylate-binding arginine cluster of TRbeta. 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 TRalpha(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.
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Banco de datos:
MEDLINE
Asunto principal:
Triyodotironina
/
Receptores de Hormona Tiroidea
/
Resistencia a Medicamentos
/
Mutagénesis Sitio-Dirigida
/
Imitación Molecular
/
Glicina
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Año:
2005
Tipo del documento:
Article