title: Discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of LRRK2.
abstract: Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice.
authors.affiliation: Novartis Institutes for BioMedical Research, Global Discovery Chemistry, CH-4002 Basel, Switzerland. thomas.troxler@novartis.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Troxler
authors.forename: Paulette
authors.initials: P
authors.lastname: Greenidge
authors.forename: Kaspar
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.forename: Peter
authors.initials: P
authors.lastname: Drückes
authors.forename: Tatjana
authors.initials: T
authors.lastname: Schweizer
authors.forename: Daniela
authors.initials: D
authors.lastname: Stauffer
authors.forename: Giorgio
authors.initials: G
authors.lastname: Rovelli
authors.forename: Derya R
authors.initials: DR
authors.lastname: Shimshek
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; C057812:indoline; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases