6A6K

Crystal structure of Estrogen-related Receptor-3 (ERR-gamma) ligand binding domain with DN201000

Summary for 6A6K

• Entry DOI: 10.2210/pdb6a6k/pdb
• Descriptor: Estrogen-related receptor gamma, 3-[(~{E})-5-oxidanyl-2-phenyl-1-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]pent-1-enyl]phenol (3 entities in total)
• Functional Keywords: sodium iodide symporter (nis), anaplastic thyroid cancer, estrogen-related receptor gamma, radioiodine therapy, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 82395.35

Authors

Yoon, H.,Kim, J.,Chin, J.,Cho, S.J.,Song, J. (deposition date: 2018-06-28, release date: 2019-04-10, Last modification date: 2023-11-22)

Primary citation

Kim, J.,Song, J.,Ji, H.D.,Yoo, E.K.,Lee, J.E.,Lee, S.B.,Oh, J.M.,Lee, S.,Hwang, J.S.,Yoon, H.,Kim, D.S.,Lee, S.J.,Jeong, M.,Lee, S.,Kim, K.H.,Choi, H.S.,Lee, S.W.,Park, K.G.,Lee, I.K.,Kim, S.H.,Hwang, H.,Jeon, Y.H.,Chin, J.,Cho, S.J.
Discovery of Potent, Selective, and Orally Bioavailable Estrogen-Related Receptor-gamma Inverse Agonists To Restore the Sodium Iodide Symporter Function in Anaplastic Thyroid Cancer.
J. Med. Chem., 62:1837-1858, 2019

PubMed 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 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.

PubMed: 30657313
DOI: 10.1021/acs.jmedchem.8b01296

Experimental method

X-RAY DIFFRACTION (2.9 Å)