Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2011) 26 S16.3

ECE2011 Symposia TSH Receptor and thyroid disorders (3 abstracts)

Small molecule TSH receptor agonists and antagonists

S Neumann & M C Gershengorn

National Institutes of Health, NIDDK, Bethesda, Maryland, USA.

TSH activates the TSH receptor (TSHR) thereby stimulating the function of thyroid follicular cells (thyrocytes) leading to biosynthesis and secretion of thyroid hormones. Because TSHR is involved in several thyroid pathologies there is a strong rationale for the design of small molecule ‘drug-like’ ligands (SMLs).

rhTSH (ThyrogenR) has been used in the follow-up of patients with thyroid cancer to increase the sensitivity for detection of recurrence or metastasis. rhTSH, which is a heterodimeric 30 kDa glycoprotein, is difficult to produce and must be administered by injection. A small molecule TSHR agonist could produce the same beneficial effects as rhTSH but with greater ease of oral administration. We developed a SML that is a full agonist at TSHR with an EC50 of 40 nM and interacts with the receptor’s serpentine domain. In primary cultures of human thyrocytes, the agonist increases mRNA levels for thyroglobulin, thyroperoxidase, sodium-iodide symporter and deiodinase type 2. More importantly for its clinical potential, this agonist elevated serum thyroxine and stimulated thyroidal radioiodide uptake in mice after its absorption from the gastrointestinal tract following oral administration.

Graves’ disease (GD) is caused by persistent, unregulated stimulation of thyrocytes by thyroid-stimulating antibodies (TSAbs) that activate TSHR. We identified the first small molecule TSHR antagonists that inhibited TSH- and TSAb-stimulated signaling. Noteworthy, in primary cultures of human thyrocytes one of the antagonists inhibited cAMP production stimulated by all thirty GD sera tested by an average of 39%.

Our results provide proof-of-principle for effectiveness of small molecule agonists and antagonists for TSHR. Chemical optimization of these SMLs will be performed in an effort to produce more potent molecules for future clinical development.

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