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

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

BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson's disease mutation (PD mutation), exhibit concentration-dependent gene silencing of pLRRK2 in the brain following intraperitoneal injection or oral administration of 50 mg/kg GNE-7915. In rats, GNE-7915 demonstrates favorable pharmacokinetic (PK) properties, including a long half-life, good oral bioavailability, and high passive permeability.

GNE-7915 exhibits excellent in vitro pharmacokinetics in human hepatocytes with minimal conversion rates. According to in vitro functional assays, GNE-7915 also acts as a moderately effective antagonist of 5-HT2B.

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.