New Drug Development Center , Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061 , South Korea.
Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute , Pusan National University , Pusan 50463 , South Korea.
J Med Chem. 2019 Feb 28;62(4):1837-1858. doi: 10.1021/acs.jmedchem.8b01296. Epub 2019 Feb 4.
An inverse agonist of estrogen-related receptor-γ (ERRγ), an orphan nuclear receptor encoded by E srrg, 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 I-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.
雌激素相关受体-γ (ERRγ) 的反向激动剂，一种由 E srrg 编码的孤儿核受体，可增强间变性甲状腺癌 (ATC) 细胞中钠碘同向转运体介导的放射性碘摄取，从而促进体外对放射性碘治疗的反应性。我们合成了强效、选择性和口服生物利用的 ERRγ 反向激动剂，并通过分析体外药理学、吸收、分布、代谢、排泄和毒性特征来评估其活性。配体和 ERRγ 复合物的 X 射线晶体学分析表明，化合物 35 与靶蛋白完全结合 (PDB 6A6K )。我们的研究结果表明，通过化合物 35 介导的碘处理基因上调，提高了 ATC 细胞对放射性碘的摄取能力，从而增强了体外对放射性碘治疗的反应性。重要的是，体内 I-正电子发射断层扫描/计算机断层扫描成像显示，化合物 35 增加了 CAL62 肿瘤对放射性碘的摄取能力。总之，这些结果表明，化合物 35 有望成为未来治疗 ERRγ 相关癌症的一种有前途的药物。
