The leucine-rich repeat kinase 2 (LRRK2) is commonly mutated in familial and sporadic Parkinson’s disease. Merck LRRK2 inhibitor-2 (MLi-2) is a potent and selective LRRK2 inhibitor with an IC50 value of 0.76nM in a purified LRRK2 kinase assay in vitro. It also exhibited high potency in a cellular assay monitoring the dephosphorylation of pSer935 LRRK2 and a radioligand competition binding assay with IC50 values of 1.4nM and 3.4nM, respectively. In mice, oral administration of MLi-2 dose-dependently reduced phosphorylation of Ser935 with the maximal suppression (>90% reduction) observed at 10mg/kg and higher. The in-diet administration of MLi-2 (3–120mg/kg/day) for 11 days significantly reduced LRRK2 protein level in the kidneys of mice. Treatment with MLi-2 (30mg/kg/day) markedly inhibited pSer935 LRRK2 in the brains of MitoPark mice at 3, 9, and 15 weeks of treatment compared with the vehicle-treated group, but did not stop the progressive motor phenotype or prevented the decline in striatal dopamine, DOPAC, or tyrosine hydroxylase levels in MitoPark mice[3].
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