molecules of the month

The Merck LRRK2 inhibitor, MLi-2, is an orally available tool compound that is structurally distinct from the LRRK2 inhibitor GNE-7915. LRRK2 had been a highly attractive target for treating Parkinson’s disease, but pulmonary toxicity observed with LRRK2 inhibition in non-human primates (NHP) cast a shadow on the utility of LRRK2 inhibitors. Since NHP studies are cost and resource-intensive, it was difficult to study the toxicity in depth. The Merck team was able to recapitulate the pulmonary toxicity in rodents with MLi-2, and found that the lung effects were due to chronic LRRK2 inhibition and were mild and readily reversible. This study provides a higher-throughput method to assess new LRRK2 inhibitor scaffolds and more broadly understand on-target effects of LRRK2 inhibition.