Highlights•Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells okabe et al.•Imatinib or nilotinib resistance was involved Src family kinase.•The BCR-ABL point mutation (E334V) was highly resistant to imatinib or nilotinib.•Ponatinib was a powerful strategy against imatinib or nilotinib resistant Ph-positive cells.

KeywordsABL kinase inhibitor resistance; Ponatinib; Point mutation

Ponatinib (AP24534) is a novel, potent multi-target inhibitor of Abl, PDGFRα, VEGFR2, FGFR1 and Src with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM and 5.4 nM, respectively.IC50 value: 0.37 nM/1.1 nM/1.5 nM/2.2 nM/5.4 nM (Abl/PDGFRα/VEGFR2/FGFR1/Src) [1]Target: Abl; multikinasein vitro: AP24534 potently inhibits native Abl, AblT315I, and other clinically important Abl kinase domain mutants with IC50 of 0.30 nM–2 nM. AP24534 doesn't inhibit Aurora kinase family members, nor does it inhibit insulin receptor or CDK2/cyclin E. AP24534 inhibits proliferation of Ba/F3 cells expressing Bcr-Abl with IC50 of 0.5 nM, as well as Ba/F3 cells expressing a range of Bcr-Abl mutants with IC50 of 0.5 nM–36 nM. The inhibition of proliferation by AP24534 is correlated with induction of apoptosis [2]. In leukemic cell lines containing activated forms of FLT3, KIT, FGFR1, and PDGFRα receptors, AP24534 potently inhibits receptor phosphorylation and cellular proliferation with IC50 of 0.3 nM to 20 nM. In MV4-11 (FLT3-ITD(+/+)) but not RS4;11 (FLT3-ITD(–/–)) AML cells, AP24534 inhibits FLT3 signaling and induced apoptosis at less than 10 nM. AP24534 inhibits viability of primary leukemic blasts from a FLT3-ITD positive AML patient with IC50 of 4 nM but not those from patients with AML expressing native FLT3 [3].in vivo: In a mouse xenograft model of Ba/F3 cells expressing native Bcr-Abl, AP24534 (2.5 mg/kg and 5 mg/kg) prolongs mice median survival. In the xenograft model of Ba/F3 Bcr-AblT315I, AP24534 (10 mg/kg–50 mg/kg) significantly suppresses tumor growth. AP24534 (30 mg/kg) decreases the phosphorylated Bcr-Abl and phosphorylated CrkL levels in the tumors [2].

Ponatinib (AP24534) is a novel, potent multi-target inhibitor of Abl, PDGFRα, VEGFR2, FGFR1 and Src with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM and 5.4 nM, respectively.IC50 value: 0.37 nM/1.1 nM/1.5 nM/2.2 nM/5.4 nM (Abl/PDGFRα/VEGFR2/FGFR1/Src) [1]Target: Abl; multikinasein vitro: AP24534 potently inhibits native Abl, AblT315I, and other clinically important Abl kinase domain mutants with IC50 of 0.30 nM–2 nM. AP24534 doesn't inhibit Aurora kinase family members, nor does it inhibit insulin receptor or CDK2/cyclin E. AP24534 inhibits proliferation of Ba/F3 cells expressing Bcr-Abl with IC50 of 0.5 nM, as well as Ba/F3 cells expressing a range of Bcr-Abl mutants with IC50 of 0.5 nM–36 nM. The inhibition of proliferation by AP24534 is correlated with induction of apoptosis [2]. In leukemic cell lines containing activated forms of FLT3, KIT, FGFR1, and PDGFRα receptors, AP24534 potently inhibits receptor phosphorylation and cellular proliferation with IC50 of 0.3 nM to 20 nM. In MV4-11 (FLT3-ITD(+/+)) but not RS4;11 (FLT3-ITD(–/–)) AML cells, AP24534 inhibits FLT3 signaling and induced apoptosis at less than 10 nM. AP24534 inhibits viability of primary leukemic blasts from a FLT3-ITD positive AML patient with IC50 of 4 nM but not those from patients with AML expressing native FLT3 [3].in vivo: In a mouse xenograft model of Ba/F3 cells expressing native Bcr-Abl, AP24534 (2.5 mg/kg and 5 mg/kg) prolongs mice median survival. In the xenograft model of Ba/F3 Bcr-AblT315I, AP24534 (10 mg/kg–50 mg/kg) significantly suppresses tumor growth. AP24534 (30 mg/kg) decreases the phosphorylated Bcr-Abl and phosphorylated CrkL levels in the tumors [2].