BCR-ABL tyrosine kinase myristoyl pocket (BCR-ABL)

The BCR-ABL tyrosine kinase myristoyl pocket is a distinct allosteric regulatory site located within the C-lobe of the ABL kinase domain (Schoepfer et al., 2014, J. Med. Chem.). In the native ABL1 protein, an N-terminal myristoyl group binds to this pocket to facilitate an autoinhibited, inactive conformation (UniProt P00519). This regulatory mechanism is lost in the BCR-ABL fusion protein, leading to constitutive kinase activity and the development of Chronic Myeloid Leukemia (CML). Therapeutic agents known as STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitors, such as asciminib, bind to this pocket to restore the inactive conformation of the enzyme (Wylie et al., 2017, Nature). This allosteric approach is particularly significant because it bypasses the ATP-binding site, allowing for efficacy against many mutations that confer resistance to traditional ATP-competitive tyrosine kinase inhibitors (Hughes et al., 2019, Leukemia). Specifically, it remains effective against the gatekeeper T315I mutation, which is a common cause of treatment failure with first- and second-generation inhibitors. By selectively targeting this unique pocket, these drugs offer a more precise mechanism of action with a potentially improved safety profile compared to multi-kinase inhibitors (FDA Scemblix Label, 2021). Clinical monitoring of patients targeting this pocket typically involves measuring BCR-ABL1 transcript levels to assess molecular response.

Other names

ABL myristoyl pocketSTAMP siteABL1 myristoyl binding siteBCR-ABL1 allosteric siteABL001 binding site

Allosteric inhibition via the STAMP (Specifically Targeting the ABL Myristoyl Pocket) mechanism, which induces a conformational change that locks the kinase in an inactive state (Wylie et al., 2017, Nature).