| Literature DB >> 23794260 |
Danielle L Aubele1, Roy K Hom, Marc Adler, Robert A Galemmo, Simeon Bowers, Anh P Truong, Hu Pan, Paul Beroza, R Jeffrey Neitz, Nanhua Yao, May Lin, George Tonn, Heather Zhang, Michael P Bova, Zhao Ren, Danny Tam, Lany Ruslim, Jeanne Baker, Linnea Diep, Kent Fitzgerald, Jennifer Hoffman, Ruth Motter, Donald Fauss, Pearl Tanaka, Michael Dappen, Jacek Jagodzinski, Wayman Chan, Andrei W Konradi, Lee Latimer, Yong L Zhu, Hing L Sham, John P Anderson, Marcelle Bergeron, Dean R Artis.
Abstract
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.Entities:
Keywords: Parkinson’s disease; computational chemistry; kinase inhibitors; medicinal chemistry; polo-like kinase-2
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Year: 2013 PMID： 23794260 DOI： 10.1002/cmdc.201300166
Source DB: PubMed Journal: ChemMedChem ISSN： 1860-7179 Impact factor: 3.466