Discovery of novel indolinone-based,potent, selective and brain penetrant inhibitors of LRRK2 |
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| Authors: | Thomas Troxler Paulette Greenidge Kaspar Zimmermann Sandrine Desrayaud Peter Drückes Tatjana Schweizer Daniela Stauffer Giorgio Rovelli Derya R Shimshek |
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| Institution: | 1. Novartis Institutes for BioMedical Research, Global Discovery Chemistry, CH-4002 Basel, Switzerland;2. Novartis Institutes for BioMedical Research, Metabolism and Pharmacokinetics, CH-4002 Basel, Switzerland;3. Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry, CH-4002 Basel, Switzerland;4. Novartis Institutes for BioMedical Research, Neuroscience, CH-4002 Basel, Switzerland |
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| 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. |
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| Keywords: | Leucine-rich repeat kinase 2 LRRK2 LRRK2 inhibitors Kinase inhibitors Parkinson’s disease |
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