Crizotinib acts as ABL1 inhibitor combining ATP-binding with allosteric inhibition and is active against native BCR-ABL1 and its resistance and compound mutants BCR-ABL1T315I and BCR-ABL1T315I-E255K

Abstract Resistance remains the major clinical challenge for therapy of Philadelphia chromosome–positive (Ph+) leukemia. With exception ponatinib, all approved tyrosine kinase inhibitors (TKIs) are unable to inhibit common “gatekeeper” mutation T315I. Here we investigated therapeutic potential crizotinib, a TKI targeting ALK and ROS1 in non-small cell lung cancer patients, which inhibited also ABL1 cell-free systems, treatment advanced therapy-resistant Ph+ By inhibiting BCR-ABL1 kinase, crizotinib efficiently suppressed growth cells without affecting Ph− cells. It was active patient-derived long-term cultures (PD-LTCs) independently responsiveness/resistance other TKIs. The efficacy confirmed vivo syngeneic mouse models BCR-ABL1- or T315I -driven chronic myeloid leukemia–like disease BCR-ABL1-driven acute lymphoblastic leukemia (ALL). Although binds ATP-binding site, it allosterically affected myristol binding pocket, site GNF2 asciminib (former ABL001). Therefore, has seemingly unique double mechanism action, on myristoylation pocket. These findings strongly suggest evaluation