HG-10-102-01 is a potent and selective inhibitor of wild-type LRRK2 and LRRK2 G2019S mutant with IC50 of 20.3 nM and 3.2 nM, respectively. HG-10-102-01 is capable of inhibiting LRRK2 phosphorylation in mouse brain. HG-10-102-01 maintains inhibition of the A2016T mutation (IC50=153.7 nM), which induces dramatic resistance to LRRK2-IN-1. HG-10-102-01 (0.03-1 uM) induced a dose-dependent inhibition of Ser910 and Ser935 phosphorylation in both wild-type LRRK2 and LRRK2[G2019S] stably transfected into HEK293 cells. HG-10-102-01 also induced dephosphorylation of Ser910 and Ser935 at a concentration of 1-3 μM in the drug-resistant LRRK2[A2016T + G2019S] and LRRK2[A2016T] mutants. HG-10-102-01 is capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg.
