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J Med Chem. 2019 Feb 28;62(4):1837-1858. doi: 10.1021/acs.jmedchem.8b01296. Epub 2019 Feb 4.

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

Author information

1
New Drug Development Center , Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061 , South Korea.
2
Department of Biomaterials Science, College of Natural Resources and Life Science/Life and Industry Convergence Research Institute , Pusan National University , Pusan 50463 , South Korea.
3
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology , Chonnam National University , Gwangju 61186 , South Korea.
4
Department of Internal Medicine, School of Medicine , Kyungpook National University , Daegu 41944 , South Korea.
5
Laboratory Animal Center , Daegu-Gyeongbuk Medical Innovation Foundation , Daegu 41061 , South Korea.

Abstract

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 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.

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