Study Rationale: LRRK2 is one of the best validated drug targets for Parkinson’s disease (PD). The LRRK2 inhibitors currently in development — called Type I inhibitors —bind to the closed, or active, state of the enzyme. Some of these inhibitors are associated with lung and kidney pathology in animal studies, suggesting a potential safety risk. In this project, we aim to develop selective inhibitors that bind to the open, inactive state of the enzyme. We will then evaluate whether these Type II inhibitors are accompanied by fewer harmful effects on the lung and kidney.
Hypothesis: The aim of this study is to assess whether Type II LRRK2 inhibitors have the potential to treat PD without causing lung or kidney damage.
Study Design: We have identified some chemicals that inhibit the open, inactive form of LRRK2; however, these compounds also inhibit enzymes other than LRRK2. We will begin by modifying these compounds to make them more selective for LRRK2 and to enhance their drug-like properties, facilitating their development as therapeutic agents. Our ultimate goal is to assess whether these Type II inhibitors are likely to be useful for the treatment of PD and determine whether they show reduced pathological effects compared to the currently studied Type I LRRK2 inhibitors.
Impact on Diagnosis/Treatment of Parkinson’s disease: If successful, our study will open a new line of research into drug discovery for PD and facilitate the development of an LRRK2 inhibitor compound with cleaner and safer profiles than those currently being progressed.
Next Steps for Development: If our Type II inhibitors give rise to reduced lung pathology in animals, we will carry out further synthesis and testing to turn these compounds into potential PD therapeutics. A key goal will be to produce compounds that are safe and can penetrate the blood-brain barrier to enter the brain.