A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRg), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer

Purpose: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy–refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRg) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC₅₀ ¼ 0.006 mmol/L), selective, and orally available ERRg inverse agonist for NIS enhancement in ATC. Experimental Design: We sought to identify better ERRg-targeting ligands and explored the crystal structure of ERRg in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumor–bearing mice were orally administered with DN200434, followed by ¹²⁴I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor–bearing mice treated with DN200434 were administered ¹³¹I (beta ray–emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRg expression status in normal tissue and ATC tissue, respectively. Results: DN200434–ERRg complex crystallographic studies revealed that DN200434 binds to key ERRg binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by ¹²⁴I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRg expression in tumors than in normal tissue, supporting ERRg as a therapeutic target for ATC. Conclusions: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.