Chemical Knockdown of LRRK2 by Small Molecule PROTACS
LRRK2 is a protein kinase that appears to be a key driver of some forms of Parkinson's disease (PD). Several potent, selective, brain-penetrant LRRK2 kinase inhibitors have been developed but have not yet ben clinically validated. LRRK2 is a large, multi-domain scaffolding protein and many PD-associated LRRK2 mutations are clustered in domains other than the kinase region. Data from genome-wide association studies indicate that up-regulation of LRRK2 expression accounts for some of the lifetime risk of developing PD. These data provide strong rationale for developing drug-like molecules that can reduce the protein levels of LRRK2 for treating PD.
In this proposal, we seek to discover if it is possible to develop small molecules that will catalyze efficient degradation (breakdown) of the LRRK2 protein in a cellular context, which will serve as a tool for studying the effects and therapeutic potential of induced LRRK2-degradation in PD.
We will use cutting-edge PROTAC technology (small molecules that bind target proteins) to generate a library of LRRK2-degraders using potent, selective, brain-penetrant LRRK2 kinase inhibitors coupled to ubiquitin (a small protein that regulates other proteins in the body) E3 ligase-recruiting ligands (molecules that bind to other molecules). These molecules will be tested and optimized for target dimerization (the binding of molecular subunits), cellular target engagement and selective protein degradation. Optimized molecules will be studied in pre-clinical models of PD to determine the effect of these molecules.
Impact on Diagnosis/Treatment of Parkinson's disease:
To develop new drugs to treat PD, specific molecular targets must be examined in experimental model systems. LRRK2 is a protein kinase that appears to be a key driver of some forms of PD, and our research aims to deliver experimental drugs that can be used to study whether degradation of LRRK2 protein results in a therapeutic effect.
Next Steps for Development:
Should this study be successful, it would deliver a small molecule able to induce selective LRRK2-protein degradation and would be suitable for use in pre-clinical experiments. The next step towards clinical development would be conduction of efficacy studies in pre-clinical models of PD.
Director of the MRC Protein Phosphorylation and Ubiquitylation Unit at MRC Protein Phosphorylation Unit, University of Dundee
Location: Dundee City, United Kingdom
Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Dana-Farber Cancer Institute
Location: Boston, Massachusetts, United States