New small molecule agonists to the thyrotropin receptor

Area of Science:

• Endocrinology
• Molecular Pharmacology

Background:

• Novel small molecular ligands (SMLs) targeting the thyrotropin receptor (TSHR) offer potential for improved molecular probes.
• These ligands are being investigated for therapeutic applications in thyroid dysfunction and thyroid cancer.

Purpose of the Study:

• To identify novel SMLs that bind to and activate the TSHR.
• To characterize the potency and signaling pathways of newly identified TSHR agonists.

Main Methods:

• A high-throughput screening system using a transcription-based luciferase-cAMP assay was employed.
• 48,224 compounds were screened, followed by rescreening and characterization of lead molecules (MS437 and MS438).
• G protein activation and gene expression studies were conducted using transfected CHO cells.

Main Results:

• Two potent TSHR-activating small molecules, MS437 and MS438, were identified from the screen.
• These molecules demonstrated no cross-reactivity with homologous receptors (LH/hCG, FSHR) and activated specific G protein pathways (Gsα, Gαq, Gα12).
• MS437 and MS438 upregulated thyroglobulin (Tg), sodium iodine symporter (NIS), and TSHR gene expression.

Conclusions:

• MS437 and MS438 exhibit pharmacotherapeutic potential, as evidenced by pharmacokinetic analysis and increased serum thyroxine levels in mice.
• These identified molecules serve as promising lead compounds for the development of novel TSHR agonists.