Development of Selective LRRK2 Inhibitors
MJFF Research Grant, 2010
LRRK2 kinase has been implicated as a potential therapeutic target for the treatment of Parkinsonís disease. The goal of our project is to make experimental drugs to test whether inhibiting LRRK2 results in therapeutic effects in models of the disease.
We have recently discovered the first selective LRRK2 inhibitor exemplified by LRRK2- inhibitor-1 (LRRK2-IN-1). We have demonstrated that LRRK2-IN-1 is biologically active and can suppress LRRK2 kinase activity. LRRK2-IN-1 has the potential to transform our understanding of LRRK2 function, in the same way that other signal transduction inhibitors have. While LRRK2-IN-1 is an excellent first-generation Ďtoolí inhibitor, it possesses some deficiencies that we seek to address in this research proposal. We would like to improve the selectivity and pharmacological properties LRRK2-IN-1 to enable its use to Ďvalidateí LRRK2 as a potential therapeutic target.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
In order to develop new drugs to treat Parkinsonís disease, 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 Parkinsonís disease and our research aims to deliver experimental drugs that can be used to study whether inhibition of LRRK2 results in a therapeutic effect.
We expect to learn whether inhibiting LRRK2 in disease models of Parkinsonís disease represents a promising approach or not. If positive results are obtained in these studies it is likely to spur clinical development of similar agents.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinsonís Disease (PD). We have developed and made available a number of selective inhibitors of LRRK2 such as LRRK2-IN-1, HG-10-102-01 and GSK2578215A which are being widely used by the PD research community to understand the normal and pathological functions of this kinase. We have also recently discovered inhibitors that exhibit selectivity for one of the mutant forms of LRRK2 called G2019S relative to the un-mutated form of the kinase. †We are currently trying to understand the structural basis for how compounds can be selective for G2019S relative to wild-type LRRK2.†
Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Dana-Farber Cancer Institute
Location: Boston, Massachusetts, United States
Director of the MRC Protein Phosphorylation and Ubiquitylation Unit at MRC Protein Phosphorylation Unit, University of Dundee
Location: Dundee City, United Kingdom