Synthesis of Leucine-rich repeat kinase 2 Degraders for Parkinson’s Disease
Leucine-rich repeat kinase 2 (LRRK2) is a gene associated with familial Parkinson’s disease (PD) and the G2019S mutation causes an increase in kinase activity. Type I ATP-competitive LRRK2 small-molecule inhibitors (SMIs) are the most predominant strategy developed to treat PD. Despite the preclinical success of several LRRK2 SMIs, dephosphorylation of biomarker sites and LRRK2 aggregation have been reported. The limitations of LRRK2 SMIs provided an opportunity to utilise known SMIs to make novel LRRK2 proteolysis-targeting chimeras (PROTACs). The synthesis of pyrrolopyrimidine-based and aminopyrimidine-based, LRRK2 SMIs and PROTACs, is described herein. The use of common chemical reactions such as nucleophilic aromatic substitutions and reductive aminations gave access to E3 ligase ligand/ linker scaffolds, for final coupling reactions to the LRRK2 SMI. The synthesised ligands and PROTACs were submitted as candidates for biological assays to examine degrader efficiency.
The poster was presented at the SCI YCP Undergraduate IP and apprenticeship symposium in Manchester on 27th June 2024.