CZC-25146 is a potentLRRK2 inhibitor with IC50 values of 4.76 and 6.87 nM for for wild-type and G2019S mutant LRRK2, respectively. It also inhibits PLK4, GAK, TNK1, CAMKK2 and PIP4K2.
Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways[2]. LRRK2 contains multiple protein-protein interacting domains, a GTPase domain, and a kinase domain. LRRK2 is implicated in many cellular processes including vesicular trafficking, autophagy, cytoskeleton dynamics, and Wnt signaling[3]. LRRK2 is highly expressed in particular immune cells and has been biochemically linked to the intertwined pathways regulating inflammation, mitochondrial function, and autophagy/lysosomal function[4]. LRRK2 mutations are the most important cause of familial Parkinson's disease, and non-selective inhibitors are protective in rodent disease models. Because of their poor potency and selectivity, the neuroprotective mechanism of these tool compounds has remained elusive so far, and it is still unknown whether selective LRRK2 inhibition can attenuate mutant LRRK2-dependent toxicity in human neurons. CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency[5]. Cortical neurons from G2019S-LRRK2 mice showed an increased vulnerability to stress insults, compared with neurons overexpressing wild-type WT-LRRK2, or non-transgenic (nTg) neurons. The exposure of LRRK2 transgenic mice to a sub-toxic dose of MPTP resulted in severe motor impairment, selective loss of dopamine neurons and increased astrocyte activation, whereas nTg mice with MPTP exposure showed no deficits[6].
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