Breakpoint cluster region-Abelson tyrosine-protein kinase 1 (Bcr-Abl) E505K mutant (Bcr-Abl E505K)

Breakpoint cluster region-Abelson tyrosine-protein kinase 1 (Bcr-Abl) is a constitutively active fusion protein resulting from the Philadelphia chromosome translocation, t(9;22)(q34;q11) [1]. This enzyme is the primary oncogenic driver in chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL), where it activates signaling pathways that promote cell survival and proliferation [1, 4]. The E505K mutation involves a substitution of glutamic acid with lysine at position 505, located within the αI-helix of the ABL kinase domain near the myristoyl binding pocket [1, 2]. This specific site is the target for STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitors like asciminib, which mimic the natural myristoyl group to lock the kinase in an inactive state [2, 3]. The E505K mutation disrupts the structural integrity of this pocket, preventing drug binding and leading to high-level clinical resistance to allosteric inhibitors [1, 3]. Consequently, this mutant represents a significant therapeutic challenge, often requiring treatment with high-potency ATP-competitive inhibitors or combination therapies to overcome resistance [3]. Monitoring for this mutation is essential in patients showing poor response to asciminib therapy to guide subsequent clinical decisions [3]. Research into this mutant continues to inform the development of next-generation allosteric inhibitors designed to accommodate or bypass pocket mutations [2]. References: [1] Wylie et al. (2017) Nature 543:733-737; [2] Schoepfer et al. (2014) J Med Chem 57:10304-10318; [3] Hughes et al. (2019) NEJM 381:2315-2326; [4] UniProt P00519.

Other names

BCR-ABL1 E505Kp210 Bcr-Abl E505KABL1 E505K mutantBcr-Abl1 myristoyl pocket mutant E505K

Allosteric inhibition of the ABL1 kinase domain by binding to the myristoyl pocket (STAMP inhibitors) or competitive inhibition of the ATP-binding site by traditional tyrosine kinase inhibitors (TKIs) [1, 3].