title: Mutant-selective thyromimetics for the chemical rescue of thyroid hormone receptor mutants associated with resistance to thyroid hormone.
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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
authors.forename: Youheng
authors.initials: Y
authors.lastname: Shi
authors.forename: Haifen
authors.initials: H
authors.lastname: Ye
authors.forename: Kristian H
authors.initials: KH
authors.lastname: Link
authors.forename: Marc C
authors.initials: MC
authors.lastname: Putnam
authors.forename: Isaac
authors.initials: I
authors.lastname: Hubner
authors.forename: Sarah
authors.initials: S
authors.lastname: Dowdell
authors.forename: John T
authors.initials: JT
authors.lastname: Koh
mesh_terms: D000085:Acetates / Q000378:metabolism; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D002264:Carboxylic Acids / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D006639:Histidine / Q000235:genetics; D006801:Humans; D008024:Ligands; D018716:Molecular Mimicry / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D010636:Phenols / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D020218:Response Elements; D037042:Thyroid Hormone Receptors beta; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000085:Acetates; D002264:Carboxylic Acids; C413355:GC 1 compound; D008024:Ligands; D010636:Phenols; D011988:Receptors, Thyroid Hormone; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; C006004:N-phthalylglycine dimethylamide; D006639:Histidine; D013972:Thyrotropin; D001120:Arginine; D003545:Cysteine; D005998:Glycine