An LRRK2 inhibitor
MLi-2 is an inhibitor of leucine-rich repeat kinase 2 (LRRK2; IC50 = 0.76 nM).1 It is greater than 100-fold selective for LRRK2 over a panel of 308 protein kinases, as well as a panel of receptors and ion channels, at 10 ?M. It increases glucocerebrosidase (GCase) activity in dopaminergic neurons differentiated from induced pluripotent stem cells generated from skin fibroblasts isolated from patients with Parkinson's disease expressing LRRK2 mutations when used at a concentration of 600 nM.2 Dietary administration of MLi-2 (30 mg/kg per day) inhibits cortical LRRK2 phosphorylation in the MitoPark mouse model of Parkinson's disease.1
1.Fell, M.J., Mirescu, C., Basu, K., et al.MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibitionJ. Pharmacol. Exp. Ther.355(3)397-409(2015) 2.Ysselstein, D., Nguyen, M., Young, T.J., et al.LRRK2 kinase activity regulates lysosomal glucocerebrosidase in neurons derived from Parkinson's disease patientsNat. Commun.10(1)5570(2019)
Animal experiment: | Mice: MLi-2 is suspended in 30% Captisol and administered in a volume of 10 mL/kg. Dose calculations are on the basis of active moiety. Mice receive MLi-2 [1-100 mg/kg; by mouth (PO)], or vehicle 1 hour prior to euthanasia by excess CO2. Immediately following euthanasia, mouse brain cortex is dissected and frozen on a steel plate over dry ice for analysis of pSer935 LRRK2 via Western Blot. Plasma and brain samples are collected and frozen for determination of MLi-2 levels by LC-MS/MS[1]. |
参考文献: [1]. Fell MJ, et al. MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition. J Pharmacol Exp Ther. 2015 Dec;355(3):397-409. | |
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