MLI-2 and Parkinson-Disease

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are the most common genetic causes of Parkinson's Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (K

Topics: Animals; Brain; Disease Models, Animal; Drug Discovery; Humans; Indazoles; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lung; Male; Mice; Molecular Docking Simulation; Mutation; Neuroprotective Agents; Parkinson Disease; Phenotype; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Rodentia; Structure-Activity Relationship

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.

Topics: Animals; Brain; Enzyme Inhibitors; Humans; Indazoles; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Molecular Docking Simulation; Parkinson Disease; Rats; Rats, Wistar