Design and synthesis of complementing ligands for mutant thyroid hormone receptor TRbeta(R320H): a tailor-made approach toward the treatment of resistance to thyroid hormone.

ABSTRACT

The thyroid hormone receptors (TR) are ligand-dependant transcription factors that regulate key genes involved in metabolic regulation, thermogenesis and development. Resistance to thyroid hormone (RTH) is a genetic disease associated with mutations to TRbeta that lack or show reduced responsiveness to thyroid hormone (triiodothyronine). Previously we reported that the neutral alcohol-based thyromimetic HY-1 can selectively restore activity to a functionally impaired form of TR associated with RTH without over-stimulating TRalpha, which has been associated with undesirable side effects. Two new series of tetrazole and thiazolidinedione based ligands were evaluated for their ability to recover potency and efficacy to three of the most common RTH-associated mutants, TRbeta(R320C), TRbeta(R320H), and TRbeta(R316H), in cell based assays. A new thiazolidinedione based ligand AH-9 was identified, which has near wild-type potency (EC(50)=0.54 nM) to TRbeta(R320C) and TRbeta(R320H). Significantly, AH-9 is equipotent toward TRalpha(wt), TRbeta(wt), TRbeta(R320C), and TRbeta(R320H), suggesting that AH-9 may have the potential to restore the normal homeostatic balance of thyroid hormone actions in patients or models harboring these mutations.