While the causes of Parkinson's disease are not clearly established, information gained from rare genetic mutations has provided insights into basic pathological mechanisms. A common genetic lesion associated with the disease is a familial mutation involving the protein kinase, LRRK2. Neuronal overexpression of the mutant LRRK2 causes excessive protein aggregation, cell death, and ultimately hyperactivity. Consequently, compounds that inhibit the mutant enzyme could provide a novel therapeutic approach to PD.
DiscoveRx Corporation proposes to develop novel high-throughput screening (HTS) assays to measure the action of small molecules at wild type and mutant forms of LRRK2. DiscoveRx will, therefore, screen compound libraries to identify selective inhibitors of the active site of LRRK2 using the HitHunterTM kinase binding assay. These compounds will be further assessed for inhibition of LRRK2 activity using the DiscoveRx ADP Quest(TM) kinase assay. Both of these approaches are presently used by biopharmaceutical companies to determine the mode of action of compounds at active as well as mutant and inactive kinases. Lead compounds identified by these assays could be useful in both validating the enzyme as a therapeutic target for PD, and as serving leads for novel therapeutics.
Unfortunately, the DiscoveRx team was unable to successfully develop an assay suitable for HTS screening of LRRK2 kinase inhibitors. Despite a year focused on developing the assay and well-thought-out troubleshooting, the team could not produce sufficient amounts of LRRK2 protein for the assay.