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Optimising Lead Series of Small Molecule Inhibitors of LRRK2 to Deliver Tool Compounds and Clinical Development Candidates

Objective/Rationale:
The exciting discovery of activating mutations in the LRRK2 kinase in a subset of familial PD patients provides a route to better understanding of signaling pathways that, when perturbed, can drive disease development. Moreover, with the emergence of small molecule inhibitors of protein kinases as a new class of efficacious drugs there is real potential to deliver novel LRRK2 inhibitor drugs that may ameliorate disease phenotypes associated with activating mutations in LRRK2.

Project Description:
Using highly effective platform screening capabilities and compound collections in GSK, we have identified novel lead series of potent and selective small molecule inhibitors of LRRK2. Progression of compounds from these series to the clinic necessitates iterative modifications to optimize against the full range of parameters required to develop a compound that is appropriate for use in cells and animal models, and generation of a compound with an appropriate tolerability profile for consequent progression to clinical trials. By integrating medicinal chemistry support funded by MJFF with the repertoire of existing assay platform capabilities and drug discovery know-how provided by GSK, we aim to deliver improved tool inhibitors for LRRK2 and a clinical candidate compound in a timely manner.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Clinical association of activating LRRK2 mutations in familial Parkinson’s patients presents a tractable opportunity to develop novel drugs to treat this condition. By funding chemistry to optimize the identified series of small molecule inhibitors of LRRK2, we will develop tool compounds with properties appropriate for use in cellular and animal models of disease. A clinical candidate compound will provide a key breakthrough for consequent clinical trials to treat LRRK2-mediated Parkinson’s disease, and evaluate broader utility in CNS disorders.

Anticipated Outcome:
By working with MJFF we will expedite development of optimized LRRK2 inhibitor compounds that will provide more suitable tool compounds for definition of LRRK2 signaling function in cells and animal models. A compound that meets all necessary requirements of a candidate for clinical use in man would be a particularly impactful outcome.


Researchers

  • Alastair D. Reith , PhD

    Stevenage United Kingdom


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