PF-06447475

PF-06447475 is a highly potent, selective and brain penetrant LRRK2 inhibitor with an IC₅₀ of 3 nM. IC50 & Target: IC50: 3 nM (LRRK2)^[1]. In Vitro: PF-06447475 inhibits LRRK2 enzyme and LRRK2 in the whole cell assay with IC₅₀s of 3 and 25 nM, respectively^[1]. 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^[2]. In Vivo: In G2019S+ rats treated with PF-06447475, a significant reduction in microgliosis to levels found in wild-type rats could be observed. The proinflammatory marker MHC-II expressed on myeloid cells but not neurons also appears to be less abundant in confocal sections in G2019S+ rats treated with PF-06447475. PF-06447475 treatment in G2019S+ rats significantly lowers the number of CD68 cells recruited to the SNpc. PF-06447475 successfully blocks the enhanced neuroinflammation associated with G2019S-LRRK2 expression. Treatment of G2019S+ rats with PF-06447475 preserves TH expression in the dorsal striatum, consistent with drug attenuating neurodegeneration in the SNpc^[3]. PF-06447475 is well tolerated in rats^[1].