Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion 
oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for 
patients with CML, with over 80% of patients treated with imatinib surviving for 
more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent 
molecular responses in both previously untreated and imatinib-resistant patients 
with CML. Studies in patients with chronic-phase CML have shown that around 50% 
of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for 
at least 2 years remain disease-free after the withdrawal of treatment. Here we 
characterize ABL001 (asciminib), a potent and selective allosteric ABL1 
inhibitor that is undergoing clinical development testing in patients with CML 
and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In 
contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl 
pocket of ABL1 and induces the formation of an inactive kinase conformation. 
ABL001 and second-generation catalytic inhibitors have similar cellular 
potencies but distinct patterns of resistance mutations, with genetic barcoding 
studies revealing pre-existing clonal populations with no shared resistance 
between ABL001 and the catalytic inhibitor nilotinib. Consistent with this 
profile, acquired resistance was observed with single-agent therapy in mice; 
however, the combination of ABL001 and nilotinib led to complete disease control 
and eradicated CML xenograft tumours without recurrence after the cessation of 
treatment.