Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• The thyrotropin receptor (TSHR) is central to thyroid gland regulation and implicated in various thyroid pathologies, including Graves' disease and thyroid cancer.
• Existing therapeutic strategies involve targeting TSHR, with both small molecules and antibodies showing inhibitory effects on TSHR signaling pathways.

Purpose of the Study:

• To review and compare low-molecular-weight compounds (LMWCs) and anti-TSHR monoclonal antibodies (mAbs) as TSHR antagonists.
• To evaluate their potential in treating TSHR-mediated thyroid diseases and for novel theranostic applications in thyroid cancer.

Main Methods:

• Review of published literature on LMWCs and mAbs targeting the TSHR.
• Analysis of their binding sites (transmembrane pocket for LMWCs, extracellular site for mAbs) and functional inhibition of TSHR signaling (cAMP, hyaluronic acid production).

Main Results:

• Both LMWCs and mAbs effectively inhibit TSHR-stimulated signaling pathways.
• mAbs offer higher affinity and longer duration but are more expensive; LMWCs are cost-effective but may be less potent.
• Anti-insulin-like growth factor 1 inhibitors also demonstrate TSHR signaling inhibition.

Conclusions:

• Monoclonal antibodies are currently the most promising TSHR-targeting agents.
• Further development of efficacious LMWCs is warranted for broader therapeutic applications.
• These agents hold potential for treating thyroid hormone resistance and for thyroid cancer theranostics.