Parkinson’s disease (PD) is a debilitating neurodegenerative disease defined by a characteristic tremor, rigidity, and slowing of movement in afflicted patients. Mutations in Leucine-rich repeat kinase 2 (LRRK2) have been associated with familial and sporadic PD. The association between LRRK2 and neurodegeneration was first identified in studies of several families that presented with an autosomal dominant, late onset form of PD. LRRK2 pathogenic variants generally increase kinase activity. For example, the most common G2019S substitution in the activation loop increases the kinase activity, likely by stabilizing the active conformation. Modulation of kinase activity by interfering with the ATP-binding in the kinase domain can be achieved with small molecule kinase inhibitors. This talk will describe the discovery of potent, selective and brain- penetrant LRRK2 kinase inhibitors and approaches towards development candidate molecules.

Discovery and development of potent, selective, and brain-penetrant LRRK2 kinase inhibitors for Parkinson's disease

2019 Fall National Meeting

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