GSK2578215A is a brain-penetrant, potent and selectiveLRRK2 inhibitor with IC50 values of 8.9 and 10.1 nM for LRRK2[G2019S] mutant and wild-type LRRK2, respectively.
Leucine-rich repeat kinase 2 (LRRK2)-dependent signaling pathway is associated with familial and sporadic Parkinson’s disease. GSK2578215A is a potent, highly selective LRRK2 kinase inhibitor with IC50 values of 10.9 nM and 8.9 nM against wild-type LRRK2 and mutant LRRK2, respectively. GSK2578215A (0.01 – 1 μM, 90min incubation) dose-dependently inhibited the phosphorylation of Ser910 and Ser935 in HEK293 cells stably expressing wild-type LRRK2 and mutant LRRK2. Similarly, in human lymphoblastoid cells derived from Parkinson’s disease patient homozygous, GSK2578215A (0.01 – 1 μM, 90min incubation) resulted in the dephosphorylation of endogenous LRRK2 at Ser910 and Ser935[3]. In SH-SY5Y cells transfected with GFP-LC3 vector, 12h treatment with 1nM GSK2578215A significantly increased the protein levels of endogenous LC3 and p62 compared to the control cells. In addition, GSK2578215A also increased the number of autophagosomes per cell and induced the accumulation of 4-HNE in SH-SY5Y cells 12h after the treatment[4]. In vivo, intraperitoneal injection of GSK2578215A (100 mg/kg) to wild-type mice caused complete dephosphorylation of LRRK2 Ser910 and Ser935 in kidney and spleen, whereas no inhibition of LRRK2 Ser910 or Ser935 phosphorylation was found in the brain[3].
作用机制
GSK2578215A is a potent, selective cellular inhibitor of LRRK2 kinase activity that binds at the hinge of the ATP site of LRRK2, inducing significant inhibition against wild-type and mutant LRRK2 both in vitro and in vivo[3].
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