FRI538 Discovery And Characterization Of Orally Bioavailable Nonpeptide Thyroid Stimulating Hormone Receptor (TSHR) Antagonists For The Treatment Of Graves’ Disease
Authors: Fowler Melissa A , Regan Collin , Zhao Jian , Coutinho Eulalia , Fleck Beth , Castellanos Anel A , Muller Eric , Johns Michael , Tang Yang , Sturchler Emmanuel , Chen Mi , Retting Kelsey , Dalvie Deepak , Betz Stephen F , Markison Stacy 
Published: October 2023

Abstract
Disclosure: M.A. Fowler: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. C. Regan: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. J. Zhao: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. E. Coutinho: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. B. Fleck: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. A.A. Castellanos: Employee; Self; Crinetics Pharmaceuticals. E. Muller: Employee; Self; Crinetics Pharmaceuticals. M. Johns: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. Y. Tang: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. E. Sturchler: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. M. Chen: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. K. Retting: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. D. Dalvie: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals. S. Markison: Employee; Self; Crinetics Pharmaceuticals. Stock Owner; Self; Crinetics Pharmaceuticals.
Graves’ disease is an autoimmune condition that affects approximately 1 in 100 people in the United States and 2-3% of the population worldwide. It is characterized by the production of autoantibodies against TSHR, and the pathology of Graves’ disease is driven by TSHR stimulatory antibodies (TSAb) that result in heightened activation of TSHR. This overstimulation results in hyperthyroidism due to excessive production of thyroid hormones. Approximately 30% of Graves’ disease patients also develop thyroid eye disease (TED or Graves’ orbitopathy) due to overactivation of TSHR in orbital fibroblasts leading to excessive production of hyaluronic acid, adipogenesis, cytokine production, and fibrosis. This can cause a myriad of debilitating symptoms including pain, swelling, blurry vision, diplopia, and proptosis. Several treatments for Graves’ hyperthyroidism are available including anti-thyroid drugs, radioactive iodine (RAI), and surgery. RAI and surgery are definitive treatments for Graves’ hyperthyroidism, but often result in hypothyroidism. In addition, none of the current treatments for Graves’ hyperthyroidism are effective in treating TED and, in some cases, such as with RAI, worsen the condition. Blocking TSHR activation directly via a TSHR antagonist may provide an important new therapeutic mechanism to treat patients with Graves’ disease that would effectively treat both the hyperthyroidism and TED. We have identified several potent and orally bioavailable nonpeptide allosteric antagonists with acceptable drug-like properties. One analog, TSHRant-1, demonstrated potent negative allosteric modulator activity at both the human and rat TSHR. To evaluate the in vivo pharmacodynamics of TSHant-1, we developed a rat model of hyperthyroidism. In this model, subcutaneous administration of the TSAb, M22, to female rats resulted in a robust and long-lasting rise in levels of the thyroid hormone thyroxin (T4). Oral administration of TSHRant-1 dose-dependently suppressed M22-stimulated T4, providing evidence that a nonpeptide allosteric antagonist of TSHR may serve as an effective treatment for Graves’ disease and associated orbitopathy (TED).
Presentation: Friday, June 16, 2023