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

The ABL kinase myristoyl pocket is a distinct allosteric regulatory site located in the C-lobe of the ABL1 kinase domain. In the native ABL1 protein, this pocket normally accommodates the N-terminal myristoyl group, which serves as a molecular switch to lock the kinase in an inactive, autoinhibited conformation (UniProt P00519). In the oncogenic BCR-ABL1 fusion protein characteristic of Chronic Myeloid Leukemia (CML), this autoinhibitory mechanism is lost, leading to constitutive kinase activity and uncontrolled cell proliferation (Nature, 2017, 543(7647):733-737). Therapeutic agents known as STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitors, such as Asciminib, bind to this site to mimic the natural myristoyl group and restore the inactive conformation (FDA Label: Scemblix). This allosteric approach is highly specific and can overcome resistance to traditional ATP-competitive tyrosine kinase inhibitors, including the gatekeeper T315I mutation (Blood, 2019, 134(Supplement_1):183). Consequently, the myristoyl pocket represents a critical therapeutic vulnerability in Philadelphia chromosome-positive leukemias.

Other names

ABL1 allosteric siteSTAMP siteMyristoyl binding siteABL kinase allosteric pocket

Allosteric inhibition by binding to the myristoyl pocket of the ABL1 kinase domain, which induces a conformational change that mimics the natural autoinhibitory state, effectively locking the kinase in an inactive conformation (Nature, 2017, 543(7647):733-737).