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Selective and Brain‐Permeable Polo‐like Kinase‐2 (Plk‐2) Inhibitors That Reduce α‐Synuclein Phosphorylation in Rat Brain
Author(s) -
Aubele Danielle L.,
Hom Roy K.,
Adler Marc,
Galemmo Robert A.,
Bowers Simeon,
Truong Anh P.,
Pan Hu,
Beroza Paul,
Neitz R. Jeffrey,
Yao Nanhua,
Lin May,
Tonn George,
Zhang Heather,
Bova Michael P.,
Ren Zhao,
Tam Danny,
Ruslim Lany,
Baker Jeanne,
Diep Linnea,
Fitzgerald Kent,
Hoffman Jennifer,
Motter Ruth,
Fauss Donald,
Tanaka Pearl,
Dappen Michael,
Jagodzinski Jacek,
Chan Wayman,
Konradi Andrei W.,
Latimer Lee,
Zhu Yong L.,
Sham Hing L.,
Anderson John P.,
Bergeron Marcelle,
Artis Dean R.
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300166
Subject(s) - kinome , neuropathology , kinase , polo like kinase , phosphorylation , neuroscience , pharmacology , chemistry , biology , microbiology and biotechnology , biochemistry , medicine , disease , cell cycle , cell
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.