Abelson murine leukemia viral oncogene homolog 1 (ABL1) (ABL1)

Abelson murine leukemia viral oncogene homolog 1 (ABL1) is a non-receptor tyrosine kinase that regulates essential cellular processes including growth, survival, and specialization [1]. In many cases of leukemia, particularly chronic myeloid leukemia (CML), a chromosomal translocation creates the BCR-ABL1 fusion protein, which is constitutively active and drives malignant transformation [2]. The myristoyl allosteric site is a deep hydrophobic pocket in the C-lobe of the ABL kinase domain that normally binds the N-terminal myristoyl group of the ABL1 protein to maintain an autoinhibited state [2, 4]. Drugs targeting this specific site, such as asciminib, act as allosteric inhibitors by mimicking the natural myristoyl group and locking the kinase in its inactive conformation [3, 4]. This mechanism, referred to as STAMP (Specifically Targeting the ABL Myristoyl Pocket), provides a therapeutic advantage by overcoming resistance mutations that occur at the orthosteric ATP-binding site, such as the T315I gatekeeper mutation [3, 4]. Sources: [1] UniProt P00519; [2] Schoepfer et al. (2014) J. Med. Chem.; [3] FDA Label for Scemblix; [4] Hughes et al. (2019) NEJM.

Other names

c-AblBCR-ABL1Proto-oncogene c-AblTyrosine-protein kinase ABL1p150JTK7

Allosteric inhibition via the Specifically Targeting the ABL Myristoyl Pocket (STAMP) mechanism, which induces an inactive conformation of the kinase domain.