title: Characterization of TAE684 as a potent LRRK2 kinase inhibitor.
abstract: Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC(50) of 7.8nM against wild-type LRRK2, 6.1nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3μM in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10mg/kg.
authors.affiliation: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Zhang
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C516714:NVP-TAE684; D011743:Pyrimidines; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases