Ponatinib (AP24534) is a imidazopyridine-based pan-inhibitor of the kinases Abl, Abl(T315I), and other clinically important Abl kinase domain mutants at potencies of 0.37 nM, 2.0 nM, and 0.30-0.44 nM, respectively. Ponatinib also potently inhibits Src, VEGFR, FGFR, and PDGFR at 5.4, 1.5, 22, and 1.1 nM, respectively, while being >1000-fold selective over IGF-1R, Aurora A, andCDK2/Cyclin E. [1] In contrast to first- (imatinib) and second-line therapies (nilotinib, dasatinib) for CML, Ponatinib shows inhibition against the T31I mutant of Bcr-Abl.

In a panel of leukemic cell lines containing activating mutations in Flt3, Kit, or activating fusions of FGFR, PDGFRa, EOL1, and KG-1, Ponatinib inhibited phosphorylation of all four receptor tyrosine kinases in a dose dependent manner with IC50 values between 0.3 and 20 nM. [2] Apoptotic induction is believed to be the mechanism by which Ponatinib inhibits FLT3-ITD to in turn inhibit MV4-11 cell viability. [2]