title: Indolinone based LRRK2 kinase inhibitors with a key hydrogen bond.
abstract: The most prevalent leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is associated with Parkinson's disease (PD). It enhances kinase activity and has been identified in both familial and sporadic cases. Kinase activity was reported to be required for LRRK2 mutants to exert their toxic effects. Hence LRRK2 kinase inhibition may be a promising therapeutic target for PD. Here we report on the discovery and characterization of indolinone based LRRK2 inhibitors. Indolinone 15b, the most potent and selective inhibitor of the present series, is characterized by an IC50 of 15nM against wild-type LRRK2 and 10nM against the LRRK2 G2019S mutant, respectively. Compound 15b was further evaluated in a kinase panel including 46 human protein kinases and in a zebrafish embryo phenotype assay, which enabled toxicity determination in whole organisms.
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt, Hessen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Göring
authors.affiliation: KU Leuven, Laboratory for Neurobiology and Gene Therapy, Leuven B-3000, Belgium.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Taymans
authors.affiliation: KU Leuven, Laboratory for Neurobiology and Gene Therapy, Leuven B-3000, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.affiliation: Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt, Hessen, Germany. Electronic address: schmidt_boris@t-online.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015394:Molecular Structure; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015027:Zebrafish / Q000196:embryology / Q000378:metabolism; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D029961:Zebrafish Proteins; C495280:LRRK2 protein, human; C551314:LRRK2 protein, zebrafish; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: LRRK2-inhibitors; Leucine-rich repeat kinase 2 (LRRK2); Parkinson’s disease; Zebrafish phenotype