Discovery of Potent, Selective, and Orally Bioavailable Estrogen-Related Receptor-γ Inverse Agonists To Restore the Sodium Iodide Symporter Function in Anaplastic Thyroid Cancer.
Jina KimJaeyoung SongHyun Dong JiEun Kyung YooJae-Eon LeeSang Bong LeeJi Min OhSeungmi LeeJi Sun HwangHeeseok YoonDong-Su KimSu-Jeong LeeMinseon JeongSungwoo LeeKyung-Hee KimHueng-Sik ChoiSang Woo LeeKeun-Gyu ParkIn-Kyu LeeSeong Heon KimHayoung HwangYong Hyun JeonJungwook ChinSung Jin ChoPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- positron emission tomography
- computed tomography
- induced apoptosis
- cell cycle arrest
- high resolution
- oxidative stress
- magnetic resonance imaging
- dual energy
- pet ct
- papillary thyroid
- squamous cell carcinoma
- poor prognosis
- binding protein
- signaling pathway
- cell proliferation
- endoplasmic reticulum stress
- pet imaging
- young adults
- mass spectrometry
- genome wide
- transcription factor
- single cell
- cell death
- photodynamic therapy
- current status
- image quality
- long non coding rna
- lymph node metastasis
- combination therapy
- replacement therapy
- genome wide identification
- drug induced
- pi k akt
- bioinformatics analysis