Funded Studies
Objective/Rationale:
Studies over the last several years have identified the protein kinase LRRK2 as a potential target for Parkinson’s disease therapeutics. While targeting kinases has been a promising area of drug discovery, efficacy and safety are often linked to how specific a drug is for the kinase(s) of interest. To this end, ensuring that any novel LRRK2 inhibitors act specifically on LRRK2, and not the closely related kinase LRRK1, will require biochemical assays for LRRK1.
Project Description:
Multiple approaches will be taken to both produce active, recombinant LRRK1 as well as develop a functional assay for characterizing inhibitors. Approaches towards protein production will include expressing versions of LRRK1 of various lengths and with different affinity tags. Biochemical assay development will involve use of enzyme assays that detect substrate phosphorylation or production of ADP, in addition to ligand binding assays.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
LRRK2 is currently of high interest as a drug target for Parkinson’s disease therapeutics. However, validating LRRK2 as a drug target and developing small molecule inhibitors will require an understanding of the selectivity of LRRK2 inhibitors, including an examination of the closest relative, LRRK1.
Anticipated Outcome:
We anticipate being able to develop recombinant LRRK1 enzyme and assay reagents suitable for characterization of the relative potency of inhibitors of LRRK2 relative to LRRK1. These reagents should aid in LRRK2 drug discovery efforts as well as provide tools to discriminate between the functions of LRRK1 and LRRK2.