Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce α-Synuclein Phosphorylation in Rat Brain
| Autor: | John P. Anderson, Dean R. Artis, Hing L. Sham, Roy K. Hom, Michael S. Dappen, Andrei W. Konradi, Simeon Bowers, Hu Pan, Robert A. Galemmo, Marc Adler, Pearl Tanaka, May Lin, Jeanne Baker, Lany Ruslim, Donald J. Fauss, Zhao Ren, Yong L. Zhu, Anh P. Truong, Danny Tam, Marcelle Bergeron, Lee H. Latimer, Paul Beroza, Jacek Jagodzinski, Heather Zhang, Michael P. Bova, George Tonn, Linnea Diep, Ruth Motter, Kent Fitzgerald, Nanhua Yao, Wayman Chan, Jennifer K. Hoffman, R. Jeffrey Neitz, Danielle L. Aubele |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Parkinson's disease Polo-like kinase Molecular Dynamics Simulation Protein Serine-Threonine Kinases Pharmacology Biology Blood–brain barrier Biochemistry Rats Sprague-Dawley Mice chemistry.chemical_compound In vivo Drug Discovery medicine Animals Humans Protein Isoforms Phosphorylation General Pharmacology Toxicology and Pharmaceutics Protein Kinase Inhibitors Alpha-synuclein Binding Sites Kinase Drug discovery Organic Chemistry Brain medicine.disease Protein Structure Tertiary Rats HEK293 Cells medicine.anatomical_structure chemistry Blood-Brain Barrier alpha-Synuclein Molecular Medicine Female Half-Life |
| Zdroj: | ChemMedChem. 8:1295-1313 |
| ISSN: | 1860-7179 |
| Popis: | Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of α-synuclein in Lewy bodies, which are one of the hallmarks of Parkinson's disease neuropathology. Potent, selective, brain-penetrant inhibitors of Plk-2 were obtained from a structure-guided drug discovery approach driven by the first reported Plk-2-inhibitor complexes. The best of these compounds showed excellent isoform and kinome-wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk-2 inhibition in vivo. One such compound significantly decreased phosphorylation of α-synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson's disease. |
| Databáze: | OpenAIRE |
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