G2019S, the most prevalent Leucine rich repeat kinase 2 (LRRK2) mutation, may upregulate LRRK2 kinase activity and is the most common known genetic cause of Parkinson’s disease (PD), and thus LRRK2 is a highly promising therapeutic target for PD. PF-06447475 is a highly potent, brain penetrant and selective LRRK2 inhibitor with IC50 of 3 nM and 11 nM for Wild type LRRK2 and G2019S LRRK2 respectively. PF-06447475 at 30 mg/kg p.o. b.i.d. was applied to G2019S+ rats for 4 weeks, stereological estimations of the number of substantia nigra pars compacta (SNpc) TH neurons showed that an ~40% loss of cells occurred in the group of G2019S+ rats treated with the control compound while there was no significant loss of TH cells in the SNpc in G2019S+ rats treated with PF-06447475. A significant reduction in microgliosis and proinflammatory marker MHC-II expressed on myeloid cells but not neurons could be observed in G2019S+ rats treated with PF-06447475, compared with those treated with control drug[3]. PF-06447475 at 1 µM protected nerve-like differentiated cells against rotenone (ROT) induced noxious effect via blocking the p-(S935)-LRRK2 kinase phosphorylation, abolishing reactive oxygen species, and reversing all ROT-induced apoptosis signaling and oxidative stress associated markers to comparable control values[4].
作用机制
PF-06447475 inhibits LRRK2 by interacting with the pyrrolopyrimidine scaffold, a well-known two-point hinge binder in kinases.
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