Indolinone based LRRK2 kinase inhibitors with a key hydrogen bond |
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Institution: | 2. Vernalis (R&D) Ltd, Cambridge, United Kingdom;1. Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, via Fossato di Mortara 17-19, 44121 Ferrara, Italy;2. Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy;3. Department of Neuroscience, Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002 Basel, Switzerland |
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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 15 nM against wild-type LRRK2 and 10 nM 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. |
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Keywords: | Parkinson’s disease Leucine-rich repeat kinase 2 (LRRK2) LRRK2-inhibitors Zebrafish phenotype |
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