c-Abl

Class

kinase inhibitor

c-Abl (ABL1) is a non-receptor tyrosine kinase that normally shuttles between the nucleus and cytoplasm, where it helps regulate cell growth, cytoskeletal remodeling, and the cellular response to genotoxic and oxidative stress. Its activity is tightly controlled by internal regulatory domains that keep the enzyme in a closed, low-activity state until specific signals trigger conformational opening and phosphorylation of downstream substrates. Dysregulated c-Abl activity is implicated in two quite different disease contexts. In certain leukemias, a chromosomal translocation fuses ABL1 to another gene, producing a constitutively active kinase that drives uncontrolled proliferation of blood cells. Separately, chronic oxidative and mitochondrial stress can activate wild-type c-Abl in neurons, where it phosphorylates proteins involved in mitochondrial quality control and protein clearance, contributing to the buildup of damaged organelles and misfolded proteins seen in neurodegenerative disease. Small-molecule kinase inhibitors that occupy the ATP-binding pocket of c-Abl block its catalytic activity, interrupting these pathological signaling cascades. The therapeutic rationale therefore spans oncology, where suppressing the fusion kinase halts malignant proliferation, and neurodegeneration, where dampening excessive c-Abl activation aims to preserve mitochondrial and protein homeostasis in vulnerable neurons.