The thyroid is a butterfly-shaped gland in the neck. The TSH receptor (TSHR) is expressed in the thyroid and stimulated by the hormone TSH. The TSHR stimulates the function of thyroid follicular cells, the thyrocytes. This leads to biosynthesis (the production of chemical compounds) and the secretion of thyroid hormones.
Several thyroid pathogens (infectious agents that cause disease) are associated with TSHR. This provides a strong argument for the design of drug-like organic small molecule ligands (SMLs) that will influence TSHR action. Our focus is the development of SMLs that agonize (stimulate) or antagonize (inhibit) TSHR action.
A TSHR agonist will be useful for patients with thyroid cancer. Iodide uptake by thyroid cells is the first step in thyroid hormone synthesis and is very important for the sensitivity of the diagnosis of thyroid cancer. A TSHR agonist stimulates uptake of iodide by thyroid cancer cells and, therefore, can help to diagnose residual cancer tissue.
On the other hand, there are patients with an autoimmune disease, Graves’ disease (GD). Antibodies in the serum of these patients permanently stimulate the TSHR, leading to an unregulated stimulation of thyroid cells. A small molecule antagonist that inhibits the continuous stimulation of the TSHR by antibodies could be useful in the therapy of GD and Graves’ ophthalmopathy (GO), a disease associated with GD in the eye.
We have provided proof-of-principle for the effectiveness of small molecule agonists and antagonists for TSHR and are now focusing on the further development of these molecules. We are preparing them for testing in animal models and for future clinical development.