GNE-7915 is a highly potent, selective and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) inhibitor.

LRRK2:1 nM(Ki), LRRK2:9 nM

表达人LRRK2蛋白质且携带G2019S帕金森病突变体的BAC转基因小鼠,腹腔注射或口服50 mg/kg GNE-7915导致大脑中pLRRK2的浓度依赖性基因沉默.GNE-7915在大鼠体内,表现出良好的PK性能,具有较长的半衰期,良好的口服利用率和高被动渗透性.

GNE-7915在人肝细胞中表现出极好的体外药代动力学,转换率最小。根据体外功能测试,GNE-7915也是中等有效的5-HT2B拮抗剂。

ALK2 kinase assay: Puri?ed recombinant ALK2 proteins, ATP, ATP[γ-32P], and dephosphorylated casein at ?nal concentrations of 2.5 nM, 6 μM, 0.05 μCi/μL , and 0.5 mg/mL, respectively, are aliquoted in kinase bu?er containing 0.2% BSA supplemented with 10 mM MnCl2 into 96-microwell plates, in combination with inhibitor compounds diluted at varying concentrations (0.01 nM to 100 μM). Positive control samples lacking inhibitor compounds, and negative controls lacking recombinant kinase, are also measured. The mixture is reacted at RT for 45 min, quenched with a ?nal concentration of 2% phosphoric acid. The reaction mixture is transferred to 96-well P81 phosphocellulose ?lter plates and bound for 5 min. The plates are washed 20 times with 150 μL of 1% phosphoric acid solution per well by vacuum manifold. Plates are dried at RT for 1 h, sealed, and assayed with Microscint 20 scintillation ?uid using a Spectramax L luminometer. Data is normalized to positive controls at 100% enzyme activity, with negative controls being subtracted as background.