Chemical Biology of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors

There is an urgent need for the development of Parkinson's disease (PD) treatments that can slow disease progression. The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to PD, and modulation of LRRK2 enzymatic activity has been proposed as a novel ther...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-09, Vol.58 (17), p.6733-6746
Main Authors: Estrada, Anthony A, Sweeney, Zachary K
Format: Article
Language:English
Subjects:
Animals
Antiparkinson Agents - chemistry
Antiparkinson Agents - pharmacokinetics
Antiparkinson Agents - pharmacology
Brain - metabolism
Guanosine Triphosphate - metabolism
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Mutation
Parkinson Disease - drug therapy
Parkinson Disease - genetics
Permeability
Protein Binding
Protein Conformation
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - chemistry
Protein-Serine-Threonine Kinases - genetics
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Summary:There is an urgent need for the development of Parkinson's disease (PD) treatments that can slow disease progression. The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to PD, and modulation of LRRK2 enzymatic activity has been proposed as a novel therapeutic strategy. In this review, we describe the bioactivity of selected small molecules that have been used to inhibit LRRK2 kinase activity in vitro or in vivo. These compounds are important tools for understanding the cellular biology of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-modifying PD therapies.
ISSN:1520-4804
DOI:10.1021/acs.jmedchem.5b00261