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.IC50 value: 1.28 nM/1.85 nM(LRRK2/G2019S LRRK2) [1]Target: LRRK2 inhibitorin vitro: CZC-54252 inhibited the activity of recombinant human wild-type LRRK2 with an IC50 ranging from ～1 to ～5 nM. The G2019S mutant was inhibited with an IC50 ranging from ～2 to ～7 nM in a TF-FRET assay. In addition, they were screened against a kinase panel of 185 kinases and exhibited good selectivity. CZC-25146 (19) inhibited five other kinases, PLK4, GAK, TNK1, CAMKK2, and PIP4K2C, with high potency only, but none of them have been classified as predictors of genotoxicity or hematopoietic toxicity [1]. G2019S LRRK2-induced human neuronal injury was attenuated by CZC-25146 with an EC50 of ~4 nM (EC50 CZC-54252 ~1 nM) and fully reversed to wild-type levels by both compounds at concentrations as low as 8 nM (1.6 nM for CZC-54252) [2].in vivo: In vivo pharmacology established a volume of distribution of 5.4 L/kg and a clearance of 2.3 L/h/kg for CZC-25146 (19). Unfortunately, it exhibited a poor brain penetration of just 4%.
References:
[1]. Ramsden N, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem Biol. 2011 Oct 21;6(10):1021-8.
[2]. Ramsden N, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem Biol. 2011 Oct 21;6(10):1021-8.