Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6
| العنوان: | Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6 |
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| المؤلفون: | H. Ümit Kaniskan, Renato Ferreira de Freitas, David Smil, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Jian Jin, Matthieu Schapira, Magdalena M. Szewczyk, Jing Liu, Fengling Li, Mohammad S. Eram, Guillermo Senisterra, Masoud Vedadi, Yudao Shen, Peter Brown |
| المصدر: | Journal of Medicinal Chemistry. 59:9124-9139 |
| بيانات النشر: | American Chemical Society (ACS), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Models, Molecular, 0301 basic medicine, Protein-Arginine N-Methyltransferases, Methyltransferase, Arginine, Cell, Chemical biology, Crystallography, X-Ray, Article, 03 medical and health sciences, Drug Discovery, medicine, Humans, Epigenetics, Enzyme Inhibitors, Drug discovery, Chemistry, HEK 293 cells, Dual inhibitor, Nuclear Proteins, 3. Good health, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, Biochemistry, Molecular Medicine |
| الوصف: | Well-characterized selective inhibitors of protein arginine methyltransferases (PRMTs) are invaluable chemical tools for testing biological and therapeutic hypotheses. Based on 4, a fragment-like inhibitor of type I PRMTs, we conducted structure–activity relationship (SAR) studies and explored three regions of this scaffold. The studies led to the discovery of a potent, selective and cell-active dual inhibitor of PRMT4 and PRMT6, 17 (MS049). As compared to 4, 17 displayed much improved potency for PRMT4 and PRMT6 in both biochemical and cellular assays. It was selective for PRMT4 and PRMT6 over other PRMTs and a broad range of other epigenetic modifiers and non-epigenetic targets. We also developed 46 (MS049N), which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. Considering possible overlapping substrate specificity of PRMTs, 17 and 46 are valuable chemical tools for dissecting specific biological functions and dysregulation of PRMT4 and PRMT6 in health and disease. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.6b01033 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::70502fd9eeb5026b08b88d95ed7a959f https://doi.org/10.1021/acs.jmedchem.6b01033 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....70502fd9eeb5026b08b88d95ed7a959f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/acs.jmedchem.6b01033 |