Objective/Rationale:
LRRK2 kinase has been implicated as a potential therapeutic target for the treatment of Parkinson’s 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.
Project Description:
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 ‘tool’ 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 ‘validate’ LRRK2 as a potential therapeutic target.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
In order to develop new drugs to treat Parkinson’s 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 Parkinson’s disease and our research aims to deliver experimental drugs that can be used to study whether inhibition of LRRK2 results in a therapeutic effect.
Anticipated Outcome:
We expect to learn whether inhibiting LRRK2 in disease models of Parkinson’s 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.
Final Outcome
Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson’s 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.