Graves' hyperthyroidism (GH) is a condition in which autoantibodies chronically activate the thyrotropin (thyroid-stimulating hormone) receptor (TSHR). TSHR is one of the few G protein-coupled receptors (GPCRs) predicted to have a signal peptide, making it a potential target for cyclotriazadisulfonamide (CADA) compounds. We sought to determine whether a small-molecule drug that selectively induces nascent protein degradation could decrease TSHR expression in vitro and in vivo at therapeutically relevant levels. We tested several CADA compounds for their ability to reduce TSHR surface expression in HEK 293 cells overexpressing human TSHR (HEK-TSHR cells) using flow cytometry. Inhibition of downstream cAMP production and thyroglobulin (Tg) secretion were measured in HEK-TSHR and human thyrocytes respectively. Follow-up studies in VGD040-treated BALB/c mice assessed plasma levels of free T4 in response to TSH stimulation. Among a number of CADA analogues, VGD040 decreased TSHR at the surface of HEK-TSHR cells. VGD040 was found to be selective towards TSHR compared to similar glycoprotein hormone receptors. In human thyrocytes, reduction of TSHR surface-expression by VGD040 decreased cAMP production and Tg secretion. Most importantly, VGD040 decreased TH secretion in mice without apparent toxicity at the effective dose studied. VGD040 is an important new lead with potential for developing safe drug treatments for GH.