c-Abl / LRRK2

Class

kinase inhibitor

c-Abl and LRRK2 are two intracellular kinases—enzymes that attach phosphate groups to other proteins to switch their activity—that have each been implicated in neurodegenerative disease, particularly Parkinson's disease. c-Abl (Abelson tyrosine kinase) is normally held in a low-activity state and becomes activated under cellular stress, including oxidative damage; once active, it phosphorylates proteins involved in cellular quality control, such as parkin, impairing their function. LRRK2 (leucine-rich repeat kinase 2) is a large, multidomain enzyme involved in vesicle trafficking, lysosomal function, and autophagy; mutations that increase its kinase activity are among the most common known genetic contributors to Parkinson's disease. Because both kinases converge on overlapping cellular processes—protein clearance, mitochondrial quality control, and neuronal survival—inhibiting both simultaneously is a rational strategy for addressing neurodegeneration through two independent but complementary points of intervention, potentially offering benefit that a single-target inhibitor might miss due to incomplete pathway coverage. Small molecules directed at this dual profile aim to reduce aberrant phosphorylation events that drive neuronal dysfunction and death, with relevance extending to other neurodegenerative conditions and, given c-Abl's separate role in cell proliferation, to oncologic contexts as well.