| Structural highlights
Function
ERR3_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 PubMed
An inverse agonist of estrogen-related receptor-gamma (ERRgamma), 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 ERRgamma-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 ERRgamma 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 (124)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 ERRgamma-related cancer in the future.
Discovery of Potent, Selective, and Orally Bioavailable Estrogen-Related Receptor-gamma Inverse Agonists To Restore the Sodium Iodide Symporter Function in Anaplastic Thyroid Cancer.,Kim J, Song J, Ji HD, Yoo EK, Lee JE, Lee SB, Oh JM, Lee S, Hwang JS, Yoon H, Kim DS, Lee SJ, Jeong M, Lee S, Kim KH, Choi HS, Lee SW, Park KG, Lee IK, Kim SH, Hwang H, Jeon YH, Chin J, Cho SJ J Med Chem. 2019 Feb 28;62(4):1837-1858. doi: 10.1021/acs.jmedchem.8b01296. Epub , 2019 Feb 4. PMID:30657313[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hentschke M, Susens U, Borgmeyer U. Transcriptional ERRgamma2-mediated activation is regulated by sentrin-specific proteases. Biochem J. 2009 Apr 1;419(1):167-76. doi: 10.1042/BJ20081556. PMID:19067653 doi:10.1042/BJ20081556
- ↑ Tremblay AM, Wilson BJ, Yang XJ, Giguere V. Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif. Mol Endocrinol. 2008 Mar;22(3):570-84. Epub 2007 Dec 6. PMID:18063693 doi:me.2007-0357
- ↑ Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A, Moras D, Renaud JP. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol Cell. 2002 Feb;9(2):303-13. PMID:11864604
- ↑ Kim J, Song J, Ji HD, Yoo EK, Lee JE, Lee SB, Oh JM, Lee S, Hwang JS, Yoon H, Kim DS, Lee SJ, Jeong M, Lee S, Kim KH, Choi HS, Lee SW, Park KG, Lee IK, Kim SH, Hwang H, Jeon YH, Chin J, Cho SJ. 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. 2019 Feb 28;62(4):1837-1858. doi: 10.1021/acs.jmedchem.8b01296. Epub , 2019 Feb 4. PMID:30657313 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01296
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