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Title: Indolinone based LRRK2 kinase inhibitors with a key hydrogen bond
Authors: Göring, Stefan ×
Taymans, Jean-Marc
Baekelandt, Veerle
Schmidt, Boris #
Issue Date: Oct-2014
Publisher: Pergamon Press
Series Title: Bioorganic & Medicinal Chemistry Letters vol:24 issue:19 pages:4630-4637
Article number: 10.1016/j.bmcl.2014.08.049
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.
ISSN: 0960-894X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group for Neurobiology and Gene Therapy
× corresponding author
# (joint) last author

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