Inhibition of LRRK2 Kinase Activity in the Treatment of Crohn's Disease

Abstract The leucine-rich repeat kinase 2 (LRRK2) gene is a genetic hotspot for gain-of-function mutations associated with various diseases such as Crohn’s and Parkinson’s disease. These mutations enhance LRRK2 kinase activity and, consequently, various inhibitors of this activity are currently being tested as treatment modalities. Here, we report studies of two novel kinase inhibitors (Termed CS-190 and CS-82) with LRRK2 inhibition activity. In vitro studies disclosed that the two inhibitors suppress LRRK2 phosphorylation as well as its ability to phosphorylate the LRRK2 targets, Rab 10 and 12; in addition, they suppress human dendritic cell production of TNFa stimulated by several known LRRK2 activators including the Dectin-1-ligand, zymosan-depleted S. cerevisiae extract. Finally, the inhibitors exhibited powerful suppression of the ability of LRRK2 to mediate NLRC4 inflammasome production of IL-1beta. These in vitro finding correlated with in vivo studies showing that IP administration of one of the kinase inhibitors (CS-82) ameliorates colitis in the DSS-colitis model as evaluated by weight loss and inflammation scores. These findings suggest that these newly developed inhibitors are potential agents for treatment of Crohn’s disease.