Selective and Brain-Permeable Polo-like Kinase-2 (Plk-2) Inhibitors That Reduce [alpha]-Synuclein Phosphorylation in Rat Brain

Polo-like kinase-2 (Plk-2) has been implicated as the dominant kinase involved in the phosphorylation of [alpha]-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 invivo. One such compound significantly decreased phosphorylation of [alpha]-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. [PUBLICATION ABSTRACT]