Resmetirom Is an Effective Thyromimetics for the Chemical Rescue of Thyroid Hormone Receptor Mutants

Abstract

Thyroid hormone receptors (TRs) predominantly consist of three isoforms: TRβ1, TRβ2, and TRα1. Mutations in TRs that reduce or eliminate their ligand-dependent functions lead to a condition known as resistance to thyroid hormone (RTH), which is a genetic disorder caused in an autosomal-dominant manner. Recently, resmetirom, a selective TRβ agonist, has showen significant promise and was approved by the United States Food and Drug Administration as the first drug for the treatment of metabolic dysfunction-associated steatohepatitis and liver fibrosis. In this study, we performed a series of assays to determine how different mutations retain the activity of resmetirom in presumed clinical practice to screen patients based on previously published 15 studies. We generated and examined the transcriptional activation of 57 mutant TRβs, to evaluate the therapeutic potential of resmetirom in treating these mutations. Resmetirom functions as a partial agonist for TRβ and has been found to recruit and interact with all cofactors, albeit significantly less effectively than T3. Consequently, our results suggest that some residues in helices 1, 3, 5, 6, 7, 10, and 11 of TRβ, are still susceptible to resmetirom binding. However, mutants of helix 12, which forms part of the dimerization interface used to bind transcriptional coactivators, are non-responsive to resmetirom. While certain mutants do not respond to lower concentrations of resmetirom, some can be rescued when higher concentrations are applied. In clinical applications, resmetirom can contribute to RTH without considering the syndrome of inappropriate secretion of thyroid-stimulating hormones by the negatively regulated gene.