Abelson tyrosine-protein kinase 1 (ABL1) myristoyl pocket (ABL1)

The ABL tyrosine kinase myristoyl pocket is a distinct allosteric regulatory site located within the C-lobe of the ABL1 kinase domain (UniProt: P00519). In healthy cells, the N-terminal myristoyl group of the ABL1 protein binds to this pocket, inducing a conformational change that stabilizes the enzyme in its inactive, autoinhibited state (Nature, 2017). However, in chronic myeloid leukemia (CML), the formation of the BCR-ABL1 fusion protein results in the loss of this myristoylated N-terminus, leading to constitutive kinase activity and uncontrolled cell proliferation (Cancer Discovery, 2014). Drugs targeting this pocket, known as STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitors, aim to restore this natural autoinhibitory mechanism. Unlike traditional ATP-competitive inhibitors like imatinib, these allosteric inhibitors bind to the myristoyl site to lock the BCR-ABL1 protein into an inactive shape (FDA Scemblix Label, 2021). This approach provides a therapeutic alternative for patients who have developed resistance to standard tyrosine kinase inhibitors, including those with the gatekeeper T315I mutation (Blood, 2019).

Other names

c-ABLABLBCR-ABL1 myristoyl binding siteSTAMP pocketAbelson murine leukemia viral oncogene homolog 1

Specifically Targeting the ABL Myristoyl Pocket (STAMP) allosteric inhibition, which mimics the natural autoinhibitory mechanism of the ABL1 protein to lock the kinase in an inactive conformation (Nature, 2017).