Tyrosine-protein kinase ABL1 (c-Abl) (ABL1)

Tyrosine-protein kinase ABL1 (c-Abl) is a ubiquitously expressed non-receptor tyrosine kinase that plays a pivotal role in integrating signals from various extracellular and intracellular stimuli to regulate cell growth, survival, and DNA damage responses [UniProt P00519]. Under physiological conditions, c-Abl shuttles between the nucleus and cytoplasm, where it modulates the actin cytoskeleton and participates in apoptosis and cell cycle arrest [NIH]. However, the reciprocal translocation between chromosomes 9 and 22 creates the BCR-ABL1 fusion gene, resulting in a constitutively active kinase that drives the pathogenesis of Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) [PubMed]. This oncogenic fusion protein promotes uncontrolled cell proliferation and resistance to apoptosis, making it a primary therapeutic target [StatPearls]. The development of small-molecule tyrosine kinase inhibitors (TKIs), such as imatinib and second-generation agents like dasatinib and nilotinib, has transformed CML into a manageable chronic condition [NIH]. More recently, allosteric inhibitors like asciminib have been developed to overcome resistance caused by mutations in the ATP-binding site, such as the T315I gatekeeper mutation [FDA]. Beyond oncology, aberrant c-Abl activation is increasingly recognized as a factor in neurodegenerative diseases like Parkinson's and Alzheimer's, where it may mediate oxidative stress-induced neuronal death [Frontiers in Aging Neuroscience].

Other names

c-AblAbelson murine leukemia viral oncogene homolog 1Abelson tyrosine-protein kinase 1p150JTK7ABLProto-oncogene c-Abl

Tyrosine kinase inhibitor (TKI); ATP-competitive inhibition of the kinase domain; Allosteric inhibition of the myristoyl pocket (STAMP).