Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2

Abstract

A potent and selective inhibitor of the kinase LRRK2 identified using an in vitro ATP-site competition binding assay also inhibits the G2019S mutant, implicated in Parkinson's disease, as well as the regulatory feedback loop where LRRK2 is phosphorylated and binds 14-3-3 protein. Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. We employed a new, parallel, compound-centric approach to identify a potent and selective LRRK2 inhibitor, LRRK2-IN-1, and demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910 and Ser935 and accumulation of LRRK2 within aggregate structures. LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease.