Merck, 438195-10MG, LRRK2 Inhibitor III, HG-10-102-01 - Calbiochem

General description
A cell-permeable 2,4-diaminopyrimidinyl compound that acts as a potent, ATP-competitive LRRK2-selective inhibitor (IC50 = 20.3, 3.2, 153.7 and 95.9 nM, respectively, against Nictide phosphorylation by recombinant human wt LRRK2 and G2019S, A2016T, G2019S/A2016T LRRK2 mutant constructs; [ATP] = 100 µM), displaying much reduced potency against MNK2 and MLK1 (IC50 = 0.6 and 2.1 µM, respectively; [ATP] = 100 µM) and little or no activity toward a panel of 136 other kinases. While both HG-10-102-01 and LRRK2-IN-1 (Cat. No. 438193) inhibit Ser910/Ser395 phosphorylation of wt and G20195 LRRK2 in human and murine cultures with similar potency (Optimal conc. 1 to 3 µM), only HG-10-102-01 is effective toward cellular phosphorylation of A2016T and G2019S/A2016T LRRK2 mutants (IC50 <3 µM). And only HG-10-102-01, but not LRRK2-IN-1 or CZC-25146 (Cat. No. 438194), can cross blood-brain-barrier and effectively inhibit brain LRRK2 phosphorylation in mice (by 40% and 70%, respectively, 1 h after i.p. dose of 30 mg/kg and ≥50 mg/kg) in vivo despite its low metabolic stability both in vitro (T1/2 = 13 min in mouse liver microsome) and in vivo (Plasma T1/2 = 0.13 h and AUClast = 74.85 h·ng/mL; 1 mg/kg via i.v.).