In vitro activity: PF-06447475 is a novel, highly potent, selective and brain penetrable LRRK2 inhibitor with IC50 of 3 nM. Leucine rich repeat kinase 2 (LRRK2) has been genetically linked to Parkinson's disease (PD) by genome-wide association studies (GWAS). PF-06447475 inhibits LRRK2 enzyme and LRRK2 in the whole cell assay with IC50s of 3 and 25 nM, respectively.

Kinase Assay: PF-06447475 inhibits LRRK2 enzyme and LRRK2 in the whole cell assay with IC50s of 3 and 25 nM, respectively.

Cell Assay: Cells incubated with PF-06447475 alone (0.5, 1, 3 μM) or in the presence of ROT significantly reduces (S935)-LRRK2 kinase phosphorylation to control. PF-06447475 has the potential for the treatment of PD. PF-06447475 inhibits LRRK2 enzyme and LRRK2 in the whole cell assay with IC50s of 3 and 25 nM, respectively. Cells incubated with PF-06447475 alone (0.5, 1, 3 μM) or in the presence of ROT significantly reduces (S935)-LRRK2 kinase phosphorylation to control. PF-06447475 significantly preserves the nucleus morphology and ΔΨm of NLCs exposed to ROT compared to untreated and control. PF-475 significantly diminishes ROT-induced ROS generation to a similar extent to cells exposed to PF-475 alone.