Ponatinib HCl CAS NO.1114544-31-8

ponatinib is a potent, orally available multi-targeted kinase inhibitor with ic₅₀ of 0.37 nm, 1.1 nm, 1.5 nm, 2.2 nm, and 5.4 nm for abl, pdgfrα, vegfr2, fgfr1, and src, respectively. ic50 & target: ic50: 0.37 nm (abl), 0.24 nm (lyn), 1.1 nm (pdgfrα), 1.5 nm (vegfr2), 2.2 nm (fgfr1), 5.4 nm (src). in vitro: ponatinib (ap24534) potently inhibits native abl (ic₅₀: 0.37 nm), abl^t315i (ic₅₀: 2.0 nm), and other clinically important abl kinase domain mutants (ic₅₀: 0.30-0.44 nm). ponatinib also inhibits src (ic₅₀: 5.4 nm) and members of the vegfr, fgfr, and pdgfr families of receptor tyrosine kinases. ponatinib potently inhibits proliferation of ba/f3 cells expressing native bcr-abl (ic₅₀: 0.5 nm). all bcr-abl mutants tested remained sensitive to ponatinib (ic₅₀: 0.5-36 nm) including bcr-abl^t315i (ic₅₀: 11 nm)^[1]. ponatinib (ap24534) inhibits the in vitro kinase activity of flt3, kit, fgfr1, and pdgfrα with ic₅₀ values of 13, 13, 2, and 1 nm, respectively. ponatinib inhibits phosphorylation of all 4 rtks in a dose-dependent manner, with ic₅₀ values between 0.3 to 20 nm. consistent with these activated receptors being important in driving leukemogenesis ponatinib also potently inhibits the viability of all 4 cell lines with ic₅₀ values of 0.5 to 17 nm. in contrast, the ic₅₀ for inhibition of rs4;11 cells which express native (unmutated) flt3, is more than 100 nm. in vivo: in a survival model in which mice are instead injected with ba/f3 bcr-abl^t315i cells, administration of dasatinib at doses as high as 300 mg/kg has no effect on survival time. by contrast, treatment with ponatinib (ap24534) prolongs survival in a dose-dependent manner. ponatinib dosed orally for 19 days at 5, 15, and 25 mg/kg prolongs median survival to 19.5, 26, and 30 days, respectively compare to 16 days for vehicle-treated mice (p<0.01 for all three dose levels). the anti-tumor activity of ponatinib (ap24534) is further assessed in a xenograft model in which ba/f3 bcr-abl^t315i cells are injected subcutaneously into mice. tumor growth is inhibited by ponatinib in a dose-dependent manner compare to vehicle-treated mice, with significant suppression of tumor growth upon daily oral dosing at 10 and 30 mg/kg (%t/c = 68% and 20%, respectively; p<0.01 for both dose levels). daily oral dosing of 50 mg/kg ponatinib causes significant tumor regression (%t/c = 0.9%, p<0.01), with a 96% reduction in mean tumor volume at the final measurement compared to the start of treatment. ponatinib is well tolerated at all efficacious dose levels for the duration of the study; maximal decreases in body weight are <5%, <5%, and <12% for the 10, 30, and 50 mg/kg dose groups, respectively, with no signs of overt toxicity. ponatinib (1-25 mg/kg) is administered orally, once daily for 28 days, to mice bearing mv4-11 xenografts. ponatinib potently inhibits tumor growth in a dose-dependent manner. administration of 1 mg/kg, the lowest dose tested, leads to significant inhibition of tumor growth (tgi=46%, p<0.01) and doses of 2.5 mg/kg or greater results in tumor regression