Abelson tyrosine-protein kinase 2 (ABL2) (ABL2)

Abelson tyrosine-protein kinase 2 (ABL2), also known as ARG (Abelson-related gene), is a non-receptor tyrosine kinase that plays a pivotal role in coordinating the actin and microtubule cytoskeletons (UniProt: P42684). It is highly homologous to ABL1 but contains unique C-terminal domains that facilitate direct binding to F-actin and microtubules, thereby regulating cell adhesion, migration, and structural morphology (PubMed: 23918371). The myristoyl pocket is a deep hydrophobic site within the kinase domain that serves as a critical allosteric regulatory switch; when occupied by a myristoyl group or a specific small-molecule inhibitor, the kinase is locked into an autoinhibited, inactive conformation (PubMed: 28846065). In various malignancies, such as breast and lung cancer, ABL2 is frequently overexpressed, driving tumor cell invasion and metastatic spread (PubMed: 21822277). Therapeutic targeting of this pocket using STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitors, such as asciminib, provides a mechanism to selectively inhibit ABL kinases without the off-target issues associated with ATP-competitive inhibitors (PubMed: 25140002). This allosteric approach is particularly valuable for overcoming resistance mutations in the ATP-binding site and for specifically modulating ABL2-mediated oncogenic signaling in solid tumors.

Other names

Abelson-related geneARGTyrosine-protein kinase ARGABLLAbelson murine leukemia viral oncogene homolog 2

Allosteric inhibition via the myristoyl pocket (STAMP mechanism)