title: Can the increasing number of newly developed leucine-rich repeat kinase 2 inhibitors validate or invalidate a potential disease-modifying therapeutic approach for Parkinson's disease?
abstract: Leucine-rich repeat kinase 2 (LRRK2) is considered an attractive therapeutic target for potential disease-modifying treatment of Parkinson's disease (PD). Both genetic and cell biological evidence have contributed to the hypothesis that LRRK2 kinase inhibition may have therapeutic potential in PD. This hypothesis was widely translated in drug discovery programs as illustrated by the growing number of patents covering newly discovered LRRK2 kinase inhibitors and emanating from at least 20 different public and private research organizations. With work still under way, this research shows the feasibility of developing potent, selective and brain permeable LRRK2 kinase inhibitors. The growing availability of these pharmacological tools should contribute to filling in the gaps in our knowledge on the safety and efficacy of LRRK2 kinase inhibition and validate/invalidate this therapeutic strategy for further development. Validation criteria should include a lack of toxic effects following long-term treatment with inhibitors as well as confirmation of target engagement in cells and animal models leading to improvement of pathological features in phenotypic assays. The state of advancement of the field of LRRK2 is such that existing biological tools and expertise can be combined with the increasing number of available LRRK2 kinase inhibitors to address these key issues.
authors.affiliation: KU Leuven Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences , Kapucijnenvoer 33 VCTB+5 bus 7001, 3000 Leuven , Belgium +32 16 332 194 ; +32 16 336 336 ; jean-marc.taymans@med.kuleuven.be.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Taymans
mesh_terms: D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010300:Parkinson Disease / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: Parkinson's disease; kinase inhibitor; leucine-rich repeat kinase 2; phenotypic assay