Endocrine Abstracts

Thyroid-stimulating hormone (TSH, thyrotropin) is an activator of the TSH receptor (TSHR) in the hypothalamic-pituitary-thyroid axis leading to biosynthesis and secretion of thyroid hormones. We have developed an orally available small molecule, allosteric TSHR agonist, E2, for follow up diagnosis of patients with thyroid cancer. This ligand could replace recombinant human TSH (rhTSH, Thyrogen) which is currently used in the clinic. In a mouse model, oral administration of E2 is as efficacious as intraperitoneal injections of rhTSH. Therefore, E2 represents a next step in the pre-clinical development of an oral drug to stimulate radioiodine uptake and/or serum thyroglobulin levels in patients with thyroid cancer. Graves’ disease (GD) is caused by persistent, unregulated stimulation of thyroid cells by thyroid-stimulating antibodies (TSAbs) that activate the TSHR. We identified the first small molecule TSHR antagonist (ANTAG3) which inhibits TSH- and TSAb-stimulated signaling. ANTAG3 is selective for TSHR because it does not inhibit activation of LH or FSH receptors, the receptors with the highest homology to TSHR within the seven transmembrane domain in which ANTAG3 binds, and it inhibits TSHR activation in the thyroid gland of mice in vivo. These findings suggested that ANTAG3 could be able to inhibit TSHR signaling in extra-thyroidal tissues that express TSHRs including orbital fibroblasts, which play a role in the pathogenesis of Graves’ ophthalmopathy (GO), a disease of the eye that is associated with GD. None of the treatment regimens for GD and GO used today are directed at the pathogenesis of these diseases. In an ideal case the same drug would treat Graves’ hyperthyroidism and GO. ANTAG3, directly acting at the TSHR, reduced TSH- and TSAb-stimulated hyaluronan (HA) production, a major component of GO, by Graves’ orbital fibroblasts. Crosstalk between the TSHR and the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) initiated by activation of TSHR may play a prominent role in the development GO. We have shown that TSHR activation alone is sufficient to stimulate HA secretion, through both IGF-1R-dependent and -independent pathways. ANTAG3 inhibited both IGF-1R-dependent and -independent pathways at all doses of the monoclonal stimulating antibody M22; whereas IGF-1R antagonist linsitinib (a small molecule kinase inhibitor) and 1H7 (inhibitory antibody) lost efficacy at high M22 doses. We propose that combination therapy targeting TSHR and IGF-1R may be an effective treatment strategy, especially for GO. We suggest that small molecule TSHR antagonists are leads for the development of orally active drugs to treat patients with Graves’ hyperthyroidism and GO.