Discovery of Potent, Selective, and Orally Bioavailable Estrogen-Related Receptor‑γ Inverse Agonists To Restore the Sodium Iodide Symporter Function in Anaplastic Thyroid Cancer

An inverse agonist of estrogen-related
receptor-γ (ERRγ),
an orphan nuclear receptor encoded by Esrrg, enhances
sodium iodide symporter-mediated radioiodine uptake in anaplastic
thyroid cancer (ATC) cells, thereby facilitating responsiveness to
radioiodine therapy in vitro. We synthesized potent, selective, and
orally bioavailable ERRγ-inverse agonists and evaluated their
activity by analyzing in vitro pharmacology and absorption, distribution,
metabolism, excretion, and toxicity profiles. X-ray crystallographic
analysis of the ligand and ERRγ complex showed that 35 completely binds to the target protein (PDB 6A6K). Our results showed
improved radioiodine avidity in ATC cells through compound 35-mediated upregulation of iodide-handling genes, leading to enhanced
responsiveness to radioiodine therapy in vitro. Importantly, in vivo 124I-positron emission tomography/computed tomography imaging
revealed that 35 increases radioiodine avidity in CAL62
tumors. Collectively, these results demonstrated that 35 can be developed as a promising treatment for ERRγ-related
cancer in the future.