CZC-54252 is a potent inhibitor of LRRK2 with IC50s of 1.28 nM and 1.85 nM for wild-type and G2019S LRRK2 respectively. Leucine-rich repeat kinase 2 (LRRK2) is a large and complex protein, with multiple enzymatic and protein-interaction domains, each of which is effected by mutations[3]. CZC-54252 inhibited the activity of recombinant human wild-type LRRK2 with an IC50 ranging from ~1 to ~5 Nm, while the G2019S mutant was inhibited with an IC50 ranging from ~2 to ~7 nM in a TF-FRET assay. LRRK2 mutations were observed in sporadic as well as familial parkinson's disease (PD)patients and have been investigated intensively, and the most common mutation in PD patients is G2019S[3]. G2019S LRRK2-induced human neuronal injury was attenuated by CZC-54252 with an EC50 of ~1 nM and fully reversed to wild-type levels at concentration as low as 1.6 nM for CZC-54252[4]. Unfortunately, it failed to cross the blood–brain barrier (BBB), displaying only 4% BBB penetration[4].
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