Tyrosine-protein kinase ABL1 (ABL1) (ABL1)

Tyrosine-protein kinase ABL1 is a non-receptor tyrosine kinase that plays a pivotal role in cellular processes such as growth, survival, and cytoskeletal remodeling [1, 2]. It is the cellular homolog of the Abelson murine leukemia virus oncogene and shuttles between the nucleus and cytoplasm to regulate DNA repair and apoptosis [2, 5]. Under normal conditions, ABL1 activity is strictly regulated; however, it becomes highly oncogenic when fused with the BCR gene through the t(9;22) chromosomal translocation, forming the Philadelphia chromosome [6, 7]. This BCR-ABL1 fusion protein possesses constitutive kinase activity that drives the pathogenesis of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) [7, 8]. Therapeutic targeting of the BCR-ABL1 oncoprotein with small-molecule tyrosine kinase inhibitors (TKIs) like imatinib has transformed CML into a manageable chronic condition [14]. Resistance to first-line TKIs often arises due to point mutations in the ABL1 kinase domain, such as the T315I gatekeeper mutation, necessitating the development of next-generation inhibitors [3, 14]. Recent advancements include allosteric inhibitors like asciminib, which target the myristoyl pocket of ABL1 to circumvent ATP-site resistance [14].

Other names

c-AblABLp150JTK7Abelson murine leukemia viral oncogene homolog 1Abelson tyrosine-protein kinase 1Proto-oncogene c-Abl

Tyrosine kinase inhibition by competitive binding to the ATP site or through allosteric binding to the myristoyl pocket.