期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 256, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2023.115475
关键词
LRRK2; Kinase inhibitor; Parkinson 's disease; Structure -activity relationship; Binding mode
Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein involved in various cellular processes and its hyperactivation leads to Parkinson's disease. Inhibiting LRRK2 is a promising therapeutic strategy for PD and recent studies have identified LRRK2 inhibitors with tissue specificity. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides valuable information for the development of novel drugs targeting LRRK2.
Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that orchestrates a diverse array of cellular processes, including vesicle transport, autophagy, lysosome degradation, neurotransmission, and mitochondrial activity. Hyperactivation of LRRK2 triggers vesicle transport dysfunction, neuroinflammation, accumulation of alpha-synuclein, mitochondrial dysfunction, and the loss of cilia, ultimately leading to Parkinson's disease (PD). Therefore, targeting LRRK2 protein is a promising therapeutic strategy for PD. The clinical translation of LRRK2 inhibitors was historically impeded by issues surrounding tissue specificity. Recent studies have identified LRRK2 inhibitors that have no effect on peripheral tissues. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides a summary of the structure and biological functions of LRRK2, along with an overview of the binding modes and structure-activity relationships (SARs) of small-molecule inhibitors targeting LRRK2. It offers valuable references for developing novel drugs targeting LRRK2.
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