MLi-2

MLi-2 is a potent, selective, and brain-penetrant small molecule inhibitor of leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2). It was developed for its high selectivity (>295-fold for over 300 kinases), and it robustly inhibits both wild-type and mutant LRRK2 associated with familial and sporadic Parkinson's disease. MLi-2 works by lowering phosphorylation (e.g., pSer935, pS1292) of LRRK2 and Rab family proteins (such as Rab12), which are linked to LRRK2 activity. It reverses pathological effects (e.g., loss of cilia, reduced neuroprotective factors, abnormal neuron signaling) in mouse models of LRRK2 mutation-driven Parkinson’s disease, including restoration of primary cilia in neuronal and glial populations and normalization of Hedgehog signaling and neurotrophic factors (like GDNF and neurturin). Chronic dosing in animals is associated with morphological changes in the lung (enlarged type II pneumocytes) but minimal kidney toxicity. Its primary clinical potential is as a disease-modifying agent for LRRK2 mutation–related Parkinson’s disease.

Other names

cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine