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Unformatted text preview: A Subtype-Selective Thyromimetic Designed to Bind a Mutant Thyroid Hormone Receptor Implicated in Resistance to Thyroid Hormone Hai Fen Ye, Kathryn E. OReilly, and John T. Koh* Department of Chemistry and Biochemistry Uni V ersity of Delaware, Newark, Delaware 19716 Recei V ed September 20, 2000 Two recent reports have demonstrated that small organic compounds (MW < 800) can act to restore function to forms of p53 and the human growth hormone receptor complex that are functionally impaired by specific genetic mutations. 1- 2 These examples of pharmacological rescue of genetically impaired proteins suggest that it may be possible to design new drugs to recover activity from many proteins known to be mutated in a number of genetically based diseases. However, thus far, com- pounds used to restore function to proteins bearing natural mutations associated with human disease are of too low potency (micromolar activity) to act as practical therapeutics. 1 Mutations to the family of nuclear and steroid hormone receptors are implicated in a diverse set of genetic diseases. 3- 4 In many cases these mutations have been shown to reside within or around the hormone-binding pocket of the receptor and disrupt normal transactivation function. 5- 7 In this work we demonstrate that by using a known receptor agonists as a structural scaffold, potent (nanomolar active) hormone analogues can be rationally designed to complement a mutant form of the human thyroid hormone receptor beta (hTR ) implicated in the genetic disease resistance to thyroid hormone (RTH) (Figure 1). The thyroid hormone receptor (TR) functions as a ligand- dependent transcriptional regulator that controls the expression of a specific set of genes involved in development and homeo- stasis in response to triiodothyronine (T3). 8- 9 There are two known TR subtypes: TR R which has been found in high concentration in skeletal muscle and brain and is closely linked to cardiac function, and TR which is undetectable in kidney and heart tissues. 10 Many RTH-associated mutations to TR are known to impair or abolish ligand-dependent transactivation function which can lead to a range of clinical presentations such as goiter, learning disabilities, impaired bone maturation, and mental retardation. 9,11 Although many mutant receptors show only reduced activity toward T3, clinical treatment of RTH with supraphysiological concentrations of T3 to recover TR activity can lead to over-stimulation of TR R which is implicated with undesirable side effects such as tachycardia and heart arhythmia....
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