Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Area of Science:

• Endocrinology
• Pharmacology
• Molecular Biology

Background:

• Seven-transmembrane-spanning receptors (7TMRs) are crucial drug targets, but small-molecule ligands for those with large, glycoprotein hormone ligands, like TSH, are scarce.
• Thyroid-stimulating hormone receptor (TSHR) agonists are needed as alternatives to recombinant human TSH for therapeutic applications.

Purpose of the Study:

• To identify and characterize novel small-molecule agonists targeting the human TSHR.
• To evaluate the in vitro and in vivo efficacy and selectivity of these agonists.

Main Methods:

• Quantitative high-throughput screening to identify initial TSHR agonists.
• Chemical modification to enhance agonist potency.
• In vitro assays using primary human thyrocytes to assess gene expression and enzyme activity.
• In vivo studies in mice to evaluate oral activity and thyroid function stimulation.
• Molecular modeling (docking) and site-directed mutagenesis to define the binding pocket.

Main Results:

• Identification of two potent and selective small-molecule TSHR agonists.
• Demonstration that agonists activate human TSHR, increasing key thyroid-related gene expression and enzyme activity in vitro.
• Confirmation of oral activity in mice, stimulating thyroid function and increasing serum thyroxine levels.
• Elucidation of agonist interaction with the TSHR serpentine and transmembrane domains.

Conclusions:

• A novel small molecule has been discovered that effectively activates the human TSHR in vitro.
• The identified agonist is orally active in vivo and stimulates thyroid function, presenting a potential therapeutic lead.
• This small-molecule TSHR agonist could serve as a future alternative to recombinant human TSH, particularly for managing thyroid cancer.