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Development of G2019S Selective LRRK2 Inhibitors for the Treatment of Parkinson’s Disease

Objective/Rationale:             
The LRRK2 kinase has been implicated as a potential therapeutic target for the treatment of Parkinson’s disease (PD). The goal of this project is to make experimental drugs to test whether inhibiting LRRK2 results in therapeutic effects in models of the disease.

Project Description:             
Researchers have recently discovered several selective LRRK2 inhibitors including LRRK2-inhibitor-1 (LRRK2-IN-1) and HG-10-102-01. LRRK2 is ubiquitously expressed and, although pre-clinical models genetically deficient in LRRK2 are viable, significant toxicities are observed in peripheral tissues (most strikingly in the kidney and lung), leading to concerns regarding the potential therapeutic utility of LRRK2 inhibitors in PD. These toxicities may be able to be avoided by an inhibitor that is selective for the G2019S mutation. Here scientists propose to develop such inhibitors, which can be used as ‘proof-of-concept’ agents to validate the notion that G2019S selective inhibitors will be efficacious and better tolerated than inhibitors of wild-type LRRK2.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
In order 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 this research aims to deliver experimental drugs that can be used to study whether inhibition of LRRK2 results in a therapeutic effect.

Anticipated Outcome:          
Researchers expect to learn whether inhibiting G2019S mutation of LRRK2 in disease models of PD represents a promising approach or not.  If positive results are obtained in these studies it is likely to spur clinical development of similar agents.


Researchers

  • Nathanael Gray, PhD

    Boston, MA United States


  • Dario Alessi, PhD

    Dundee United Kingdom


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