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[그림] ERRγ 조절 기전 후보물질 (DN201000) 개발 관련 발표 논문 표지

[그림] 개발 후보물질의 ERRγ 표적 단백질 결합 구조 및 동물 효능 결과

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.

Author information

Kim J1, Song J1, Ji HD, Yoo EK, Lee JE2, Lee SB1, Oh JM, Lee S, Hwang JS1, Yoon H1, Kim DS1, Lee SJ1, Jeong M1, Lee S1, Kim KH1, Choi HS3, Lee SW, Park KG4, Lee IK4, Kim SH1, Hwang H1, Jeon YH5, Chin J1, Cho SJ1.
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.