Abstract

One of the most promising therapeutic targets for potential diseasemodifying treatment of Parkinson’s disease (PD) is leucine-rich repeat kinase 2 (LRRK2). Specifically, targeting LRRK2’s kinase function has generated a lot of interest from both industry and academia. This work has yielded several published studies showing the feasibility of developing potent, selective and brain permeable LRRK2 kinase inhibitors. The availability of these experimental drugs is contributing to filling in the gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition. Recent studies of LRRK2 kinase inhibition in preclinical models point to potential undesired effects in peripheral tissues such as lung and kidney. Also, while strategies are now emerging to measure target engagement of LRRK2 inhibitors, there remains an important need to expand efficacy studies in preclinical models of progressive PD. Future work in the LRRK2 inhibition field must therefore be directed towards developing molecules and treatment regimens which demonstrate efficacy in mammalian models of disease in conditions where safety liabilities are reduced to a minimum.

Keywords: kinase inhibitor, LRRK2, Parkinson’s disease, phenotypic assay.

Graphical Abstract