Development of a highly potent and selective degrader of LRRK2
John M Hatcher1, Monika Zwirek2, Adil R Sarhan3
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Longwood Center LC-2209, Boston, MA 02115, USA.
Abstract:
The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in leucine-rich repeat kinase 2 (LRRK2) are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. Furthermore, LRRK2 function as a scaffolding protein in several pathways has been implicated as a plausible mechanism underlying neurodegeneration caused by LRRK2 mutations. Given that both the kinase activity and scaffolding function of LRRK2 have been linked to neurodegeneration, we developed proteolysis-targeting chimeras (PROTACs) targeting LRRK2. The degrader molecule JH-XII-03-02 (6) displayed high potency and remarkable selectivity for LRKK2 when assessed in a of 468 panel kinases and serves the dual purpose of eliminating both the kinase activity as well as the scaffolding function of LRRK2.
Insights
Researchers developed a novel PROTAC molecule to target Leucine-Rich Repeat Kinase 2 (LRRK2) in Parkinson's Disease (PD). This molecule effectively reduces LRRK2 kinase activity and scaffolding functions, offering a potential new therapeutic strategy for PD.
Area of Science:
- Neurodegenerative medicine
- Molecular biology
- Drug discovery
Background:
- Parkinson's Disease (PD) lacks disease-modifying therapies.
- Genetic mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are PD risk factors.
- Mutated LRRK2 exhibits increased kinase activity and neurotoxicity, and its scaffolding function contributes to neurodegeneration.
Purpose of the Study:
- To develop novel therapeutics targeting both kinase and scaffolding functions of LRRK2.
- To create proteolysis-targeting chimeras (PROTACs) for LRRK2 degradation.
Main Methods:
- Development of PROTAC molecules designed to degrade LRRK2.
- Assessment of a specific PROTAC molecule (JH-XII-03-02) for potency and selectivity against a panel of 468 kinases.
Main Results:
- The PROTAC molecule JH-XII-03-02 demonstrated high potency and selectivity for LRRK2.
- This molecule effectively eliminates both the kinase activity and scaffolding function of LRRK2.
Conclusions:
- PROTACs targeting LRRK2 represent a promising therapeutic strategy for Parkinson's Disease.
- JH-XII-03-02's dual action on LRRK2 kinase and scaffolding functions offers a novel approach to neuroprotection in PD.
