Structural Insights and Development of LRRK2 Inhibitors for Parkinson's Disease in the Last Decade

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

G2019S mutation; LRRK2; Parkinson’s disease; kinase inhibitors; neurodegeneration.