Novel LRRK2 Kinase Inhibitors Enhance Phosphorylation and Restore Adapter Protein Binding in LRRK2 Variants

Series B LRRK2 inhibitors (based on GNF-7) enhanced phosphorylation of interdomain heterologous phosphosites and restored 14-3-3 binding in LRRK2 variants with suppressed phosphorylation.

• Why it matters: Type I kinase inhibitors reduce hyperphosphorylation but bind the active, closed kinase conformation, potentially disrupting other LRRK2 functions that may contribute to Parkinson’s disease risk.
• What they did: Two inhibitor series were tested—hesperadin-based (series A) and GNF-7-based (series B)—showing inhibition of LRRK2 kinase activity in biochemical and cellular assays while differing in effects on other LRRK2 functions.
• The result: The series B chemotypes provide tools to dissect consequences of different inhibitor-bound LRRK2 conformations and support conformation-selective inhibition as a therapeutic strategy for PD.