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

The ABL myristoyl pocket is a deep hydrophobic cavity in the C-lobe of the ABL1 kinase domain, normally occupied by the covalently attached myristoyl group of ABL1 isoform 1b. Occupancy of this pocket by the myristoyl group or by small-molecule drugs induces a bent conformation in the αI helix, promoting the docking of regulatory domains (SH2/SH3), resulting in autoinhibition of kinase activity. In the disease state, most notably in BCR-ABL1-driven CML, kinase activity is dysregulated. Allosteric inhibitors such as asciminib bind specifically to this pocket, restoring autoinhibition and suppressing aberrant kinase activity. This mechanism is distinct from traditional ATP-competitive TKIs and allows for selectivity and efficacy even in cases with resistance mutations such as T315I. The ABL myristoyl pocket is thus a validated therapeutic target and forms the basis for a new class of kinase inhibitors.

Other names

Abl myristoyl pocketABL1 myristoyl pocketABL regulatory pocketSTAMP site (Specifically Targeting the ABL Myristoyl Pocket)

Allosteric inhibition: drugs bind to the myristoyl pocket, stabilizing the inactive kinase conformation. Forces autoinhibition distinct from ATP-competitive inhibition.