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Crystal structure of Estrogen Related Receptor-3 (ERR-gamma) ligand binding domain with DN200434
Structural highlights
FunctionERR3_HUMAN Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity).[1] [2] [3] Publication Abstract from PubMedPURPOSE: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy-refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRgamma) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC50 = 0.006 muM), selective, and orally available ERRgamma inverse agonist for NIS enhancement in ATC. EXPERIMENTAL DESIGN: We sought to identify better ERRgamma-targeting ligands and explored the crystal structure of ERRgamma in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression as well as radioiodine avidity was examined. ATC tumor-bearing mice were orally administered with DN200434, followed by (124)I-positron emission tomography/computed tomography (PET/CT). For radioiodine therapy, ATC tumor-bearing mice treated with DN200434 were administered (131)I (beta ray-emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histological analysis was performed to evaluate ERRgamma expression status in normal tissue and ATC tissue, respectively. RESULTS: DN200434-ERRgamma complex crystallographic studies revealed that DN200434 binds to key ERRgamma binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by (124)I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histological findings of patients with ATC showed higher ERRgamma expression in tumors than in normal tissue, supporting ERRgamma as a therapeutic target for ATC. CONCLUSIONS: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers. A novel orally active inverse agonist of estrogen-related receptor gamma (ERRgamma), DN200434, a booster of NIS in anaplastic thyroid cancer.,Singh TD, Song J, Kim J, Chin J, Ji HD, Lee JE, Lee SB, Yoon H, Yu JH, Kim SK, Yoon GS, Hwang H, Lee HW, Oh JM, Lee SW, Lee J, Choi HS, Na SY, Choi WI, Park YJ, Song YS, Kim YA, Lee IK, Cho SJ, Jeon YH Clin Cancer Res. 2019 Apr 22. pii: 1078-0432.CCR-18-3007. doi:, 10.1158/1078-0432.CCR-18-3007. PMID:31010838[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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