 Ponatinib AP24534 is a third generation tyrosine kinase inhibitor targeting the BCR-ABL tyrosine kinase domain. Ponatinib was rationally designed with an extensive network of optimized molecular contacts and triple bonds to accommodate the T315I mutation, a major cause of resistance to tyrosine kinase inhibitors in chronic and advanced phase chronic myelogenous leukemia CML. Ponatinib also inhibits SRC IC50: 5.4 nM and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases OHare T, Cancer Cell 2009. Despite low activity against FLT3 based on the IC50 value FLT3 IC50: 12.6 nM compared to BCR IC50: 0.37 nM, ponatinib has recently been reported to have significant cellular activity against the MV4-11 cell line which harbors an FLT3-ITD activating mutation. Ponatinib-induced apoptosis was maximal at 10 nM in vitro and a single dose of 5 and 10 mgkg had a strong inhibitory effect in vivo in mice bearing MV4-11 xenografts. Primary blast cells from 4 FLT3-ITD AML patients were also tested and ponatinib reduced their viability IC50: 4 nM whereas no activity was shown on FLT3-ITD-negative blast cells Gozgit JM et al. Mol Cancer Ther 2011. 