Abelson tyrosine-protein kinase (ABL)

Abelson tyrosine-protein kinases (ABL) are a family of non-receptor tyrosine kinases, primarily consisting of ABL1 and ABL2, that play pivotal roles in integrating signals for cell growth, survival, and cytoskeletal organization [1, 5]. While ABL kinases are essential for normal cellular function, the ABL1 gene is most famous for its involvement in the t(9;22) chromosomal translocation, which creates the BCR-ABL1 fusion protein, also known as the Philadelphia chromosome [2, 3]. This chimeric protein is constitutively active, driving the pathogenesis of Chronic Myeloid Leukemia (CML) and a subset of Acute Lymphoblastic Leukemia (ALL) by activating proliferative pathways such as PI3K/AKT and RAS/MAPK [3, 5]. The therapeutic landscape for ABL-driven malignancies was revolutionized by the development of imatinib, the first-in-class tyrosine kinase inhibitor (TKI) [3]. Current clinical management involves multiple generations of TKIs designed to overcome resistance mutations, such as the T315I gatekeeper mutation, and includes novel allosteric inhibitors like asciminib that target the myristoyl pocket (STAMP) for improved specificity [4, 6].

Other names

ABL1ABL2c-AblAbelson murine leukemia viral oncogene homologp150BCR-ABL1Abelson-related gene (ARG)

Small-molecule inhibition of the kinase domain through ATP-competitive binding or allosteric binding to the myristoyl pocket, which stabilizes the kinase in an inactive conformation and prevents downstream oncogenic signaling [3, 4, 6].