Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene is tightly linked to Parkinson’s disease (PD) as its missense mutation, G2019S, is frequently found in not only familial but also sporadic PD. LRRK-2IN1 inhibits both wild-type and G2019S mutant LRRK2 kinase activity with IC50 values of 13 nM and 6 nM, respectively[4]. LRRK2-IN-1 at 100 nM and 500 nM could protect against G2019S-associated cellular toxicity and significantly improve cell survival in human SH-SY5Y neuroblastoma cell line transfected with G2019S -LRRK2 along. It was also found that treatment of LRRK2-IN1 during both pre- and post-symptomatic stages significantly protect dopamine neurons against neurodegeneration caused by G2019S in C. elegans [5]. AsPC-1 cells treated with 0.5 μM- and 5.0 μM-LRRK2-IN-1 showed decreased expression of epithelial-to-mesenchymal transition (EMT) factors and WNT1, increased expression of E-cadherin. Consistently, there was a dose-dependent reduction in the invasive potential of AsPC-1 cells 24 h post LRRK2-IN-1 treatment, with an approximately 70% decrease in invasive potential following 5 μM treatment. AsPC-1 tumor xenografts injected with LRRK2-IN-1(100 mg/kg, 4weeks) showed more than 50% decreases in tumor volume and weight[6].
作用机制
LRRK2-IN-1 inhibits wild-type and G2019S mutant LRRK2 kinase in an ATP-competitive manner.
LRRK2-IN-1 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
HEK293 cells
Function assay
Inhibition of LRRK2 G2019S mutant expressed in HEK293 cells using nictide and ATP as substrate, IC50=0.006 μM
22335897
HEK293 cells
0.03-3 μM
Function assay
90 mins
Inhibition of wild-type LRRK2 phosphorylation at Ser935 expressed in HEK293 cells at 0.03 to 3 uM after 90 mins by immunoblot analysis
22335897
lymphoblastoid cells
0.03 to 3 uM
Function assay
90 mins
Inhibition of LRRK2 in human lymphoblastoid cells assessed as inhibition of Ser910 autophosphorylation at 0.03 to 3 uM after 90 mins by immunoblot method
Inhibition of LRRK2 G2019S mutant expressed in HEK293 cells using nictide and ATP as substrate, IC50=0.006 μM
22335897
HEK293 cells
0.03-3 μM
Function assay
90 mins
Inhibition of wild-type LRRK2 phosphorylation at Ser935 expressed in HEK293 cells at 0.03 to 3 uM after 90 mins by immunoblot analysis
22335897
lymphoblastoid cells
0.03 to 3 uM
Function assay
90 mins
Inhibition of LRRK2 in human lymphoblastoid cells assessed as inhibition of Ser910 autophosphorylation at 0.03 to 3 uM after 90 mins by immunoblot method
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