RN341 is a LRRK2-specific type II kinase inhibitor (IC50 of 296 nM). It prevents the phosphorylation of LRRK2 by stabilizing an open conformation, thereby avoiding S935 dephosphorylation. Additionally, RN341 rescues LRRK2-mediated kinesin motility blockage by preventing microtubule binding. This compound effectively inhibits both wild-type and G2019S LRRK2 at the cellular level, offering a novel avenue for Parkinson's disease research.

RN341 (Compound IRN341) specifically inhibits the phosphorylation of LRRK1/2 substrates at concentrations of 0.25-10 μM over 4 hours, without affecting the biomarker site S935. When tested at 1-10 μM in an activity screen of 350 kinases, RN341 significantly reduces the residual activity of 10 kinases to below 30% at higher concentrations. The EC50 values for RN341 at 0.01-10 μM indicate that out of 12 identified off-target kinases, only 4 (STK10, MAPK14, JNK2, and TTK) are inhibited, with EC50 values in the submicromolar range (<5 μM).