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.