HY-1

The authors demonstrate that by using a known receptor agonists as a structural scaffold, potent (nanomolar active) hormone analogs can be rationally designed to complement a mutant form of the human thyroid hormone receptor beta (hTRβ) implicated in the genetic disease resistance to thyroid hormone (RTH).The RTH-associated mutation, TRβ (R32OC) exhibits a reduced affinity for triiodothyronine (T3).Furthermore, concentrations of T3 required to significantly activate the mutant TRβ(R32OC), impart an undesirable saturating response to TRα-mediated transactivation (EC₅₀ = 0.14±0.24 nM).Therefore, compounds having high affinity and selectivity for mutant forms of TRβ over the α-subtype are sought for RTH therapy.The potent nonhalogenated thyromimetic GC1 shows a significantly reduced activity toward the mutant receptor TRβ(R32OC) (EC₅₀ = 37.7±10.8 nM) than to the TRβ(Wt) (EC₅₀ 3.67±1.1 nM) in cultured cells and is therefore no longer selective for the mutant β-subtype over TRα(Wt) (EC₅₀ = 6.6±1.0 nM).On the basis of site-models generated from the coordinates of the T3/TRβ crystal structure, the authors designed the neutral alc. HY1 as a potential subtype-selective ligand for the mutant receptor hTRβ(R320C).Assays of transactivation function show that HY1 (EC₅₀ = 7.01±3.0 nM) is 5-times more potent an agonist toward TRβ(R32OC) than the parent compound GC1, indicating that the authors' designed ligand was indeed more potent than GC1.Importantly, HY1 is also capable of eliciting substantial transactivation response from the mutant TRβ at concentrations that show only partial activation of TRα (EC₅₀ = 37.69±10.4 nM) and TRβ (EC₅₀ = 32.05±8.7 nM).Although even greater levels of subtype-selectivity may be desirable, these data suggest that HY1 may have unique potential as a therapeutic capable of recovering activity from the mutant form of TRβ while potentially avoiding the undesirable side effects associated with TRα over stimulation.This work demonstrates that by making compensatory modifications to known hormone agonists, new, highly potent ligands can be made which are selective for mutant receptors implicated in human disease.Although in principle this general strategy may require a unique drug to be designed for each mutation associated with a particular disease, as demonstrated by this work on hTRβ, similar design strategies may be used to complement structurally similar mutations in related receptors.