title: Identification of chemicals to inhibit the kinase activity of leucine-rich repeat kinase 2 (LRRK2), a Parkinson's disease-associated protein.
abstract: Parkinson's disease (PD) is a late-onset neurodegenerative disease which occurs at more than 1% in populations aging 65-years and over. Recently, leucine-rich repeat kinase 2 (LRRK2) has been identified as a causative gene for autosomal dominantly inherited familial PD cases. LRRK2 G2019S which is a prevalent mutant found in familial PD patients with LRRK2 mutations, exhibited kinase activity stronger than that of the wild type, suggesting the LRRK2 kinase inhibitor as a potential PD therapeutics. To develop such therapeutics, we initially screened a small chemical library and selected compound 1, whose IC(50) is about 13.2 μM. To develop better inhibitors, we tested five of the compound 1 derivatives and found a slightly better inhibitor, compound 4, whose IC(50) is 4.1 μM. The cell-based assay showed that these two chemicals inhibited oxidative stress-induced neurotoxicity caused by over-expression of a PD-specific LRRK2 mutant, G2019S. In addition, the structural analysis of compound 4 suggested hydrogen bond interactions between compound 4 and Ala 1950 residue in the backbone of the ATP binding pocket of LRRK2 kinas domain. Therefore, compound 4 may be a promising lead compound to further develop a PD therapeutics based on LRRK2 kinase inhibition.
authors.affiliation: Institute for Brain Science and Technology, Inje University, Gaegumdong, Busanjingu, Busan, South Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Yun
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Heo
authors.forename: Hyun Ha
authors.initials: HH
authors.lastname: Kim
authors.forename: Nam
authors.initials: N
authors.lastname: DooKim
authors.forename: Wongi
authors.initials: W
authors.lastname: Seol
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases