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

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. Gets into your head: By using a structure‐guided drug discovery approach, highly selective brain‐penetrant Plk‐2 inhibitors were designed with the use of an interesting aromatic edge–face interaction as a potency–selectivity determinant. An analogue from this work lowered phosphorylated α‐synuclein levels in vivo on oral dosing, demonstrating successful target engagement in the rat brain and paving the way for proof‐of‐concept studies in rodent models of Parkinson's disease.