Targeting the thyroid-stimulating hormone receptor with small molecule ligands and antibodies

Abstract

Introduction The thyroid-stimulating hormone receptor (TSHR) is the essential molecule for thyroid growth and thyroid hormone production. Since it is also a key autoantigen in Graves’ disease and is involved in thyroid cancer pathophysiology, the targeting of the TSHR offers a logical model for disease control. Areas covered We review the structure and function of the TSHR and the progress in both small molecule ligands and TSHR antibodies for their therapeutic potential. Expert opinion Stabilization of a preferential conformation for the TSHR by allosteric ligands and TSHR antibodies with selective modulation of the signaling pathways is now possible. These tools may be the next generation of therapeutics for controlling the pathophysiological consequences mediated by the effects of the TSHR in the thyroid and other extrathyroidal tissues.

Inhibiting thyrotropin/insulin-like growth factor 1 receptor crosstalk to treat Graves' ophthalmopathy: studies in orbital fibroblastsin vitro

“…Our results reveal that ANTAG3 retains efficacy at all concentrations of the M22 concentration‐response. Although there is no therapy targeting TSH receptors currently under clinical evaluation, there are low MW compounds in preclinical development (Gershengorn and Neumann, ; Davies and Latif, ).…”

Critical Differences between Induced and Spontaneous Mouse Models of Graves’ Disease with Implications for Antigen-Specific Immunotherapy in Humans

“…Several novel therapeutic approaches for human Graves’ disease are being tested including small molecule inhibitors of TSHR function (4,5), monoclonal TSHR antibodies that block the function of thyroid stimulating autoantibodies (TSAb)(6), and inhibitors of components of the adaptive immune system, such as rituximab which target B-lymphocytes (7,8). Most important, however, even if successfully introduced into the pharmacopeia, these approaches may treat, but will not cure Graves’ disease, and non-specific immunological inhibitors have potentially severe side effects.…”

Targeting the TSH receptor in thyroid cancer

“…Although encoded by a single gene, the gene product undergoes post-translational cleavage into an extracellular A-subunit and a largely intracellular B-subunit linked by disulfide bonds, with the exclusion of a 50 amino acid C-peptide region (Rapoport & McLachlan 2016). The A-subunit contains multiple binding sites for TSH within a leucinerich 'binding pocket', which undergoes conformational change after binding of TSH or stimulatory autoantibodies, resulting in receptor activation (Davies & Latif 2015).…”

“…Such small-molecule antagonists of TSHR have significant parallel interest in the treatment of Graves' disease, where stimulatory autoantibodies against TSHR induce marked hyperthyroidism. Davies and Latif (2015), in their recent appraisal of this issue, identify several molecules that have been trialed over the last decade. To date, however, no molecule has been able to achieve sufficient specificity in vivo to substantially inhibit TSHR signaling (inhibition of cAMP production in orbital fibroblasts was 50% in one study (Neumann et al 2012)).…”