Selective Inhibitors of G2019S-LRRK2 Kinase Activity

Pathogenic
variants in the leucine-rich repeat kinase 2 (LRRK2)
gene have been identified that increase the risk for developing Parkinson’s
disease in a dominantly inherited fashion. These pathogenic variants,
of which G2019S is the most common, cause abnormally high kinase activity,
and compounds that inhibit this activity are being pursued as potentially
disease-modifying therapeutics. Because LRRK2 regulates important
cellular processes, developing inhibitors that can selectively target
the pathogenic variant while sparing normal LRRK2 activity could offer
potential advantages in heterozygous carriers. We conducted a high-throughput
screen and identified a single selective compound that preferentially
inhibited G2019S-LRRK2. Optimization of this scaffold led to a series
of novel, potent, and highly selective G2019S-LRRK2 inhibitors.