GSK2578215A

GSK2578215A is a potent and highly selective LRRK2 inhibitor, which exhibits IC₅₀s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. In Vitro:GSK2578215A (0-1 μM, 90 min) inhibits Ser910 and Ser935 phosphorylation in HEK293 cells stably transfected with wild-type LRRK2 and LRRK2[G2019S], as well as in mouse Swiss 3T3 cells^[1].
GSK2578215A (1 nM, 12 h) induces autophagy (increased level of LC3 and p62 protein) in SH-SY5Y cells^[2].
GSK2578215A (1 nM, 12 h) induces Drp1-mediated mitochondrial fission in SH-SY5Y cells, and induces mitophagy (12 and 24 h)^[2].
GSK2578215A (1 nM, 24 h) induces oxidative stress, indicated by the accumulation of 4-HNE in SH-SY5Y cells, and induces apoptotical cell death^[2].
GSK2578215A (1 μM, 24 h) inhibits homologous recombination in OVCAR8 cells^[3].
In Vivo:GSK2578215A (5 mg/kg, i.p.) with Olaparib (HY-10162) (50 mg/kg, i.p., T.I.W for 3 weeks) effectively inhibits the tumor growth in mice bearing OVCAR8 xenografts^[3].
GSK2578215A (IV, 1 mg/kg, or PO, 10 mg/kg) achieves an exposure in the brain with a brain to plasma ratio of 1.4 (IV) and 2.4 (PO), and shows low oral bioavailability (IV, 12.2%), a half-life of 1.14 h (IV) and plasma exposure (PO, 635.3 h ng/mL, AUC_last)^[1].