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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. 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 alpha-synuclein levels invivo 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.
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Tetrahydrofuran – Wikipedia,
Tetrahydrofuran | (CH2)3CH2O – PubChem