Ponatinib

Ponatinib is a potent multi-target kinase inhibitor with antiangiogenic and antineoplastic activities. It targets protein tyrosine kinases (PTK), which catalyze the transfer of ATP-gamma-phosphate to the tyrosine residues of the substrate proteins. Tyrosine kinase inhibitors (TKIs) compete with ATP for the ATP binding site of PTK and reduce tyrosine kinase phosphorylation, thereby inhibiting cancer cell proliferation. Ponatinib is an Bcr-Abl tyrosine kinase inhibitor in biochemical assays. Ponatinib also inhibits other tyrosine kinases associated with vascular endothelial growth factor receptors (Flk-1 (VEGFR2) with IC50 = 1.5nM) and fibroblast growth factor receptors (FGFR1 with IC50 = 2.2nM). As a multitargeted pan-FGFR inhibitor, it inhibited cell growth with GI50 values of 7 to 181nM in a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung and colon) and containing dysregulated FGFRs. Ponatinib exhibits inhibitory activity against PDGFRa, c-Src and c-Kit (IC50 = 1.1, 5.4 and 12.5nM, respectively). In addition, it inhibits RET (native and drug-insensitive V804M/L mutant), TIE2 and FMS-related tyrosine kinase receptor-3 (FLT3). Ponatinib enhances anticancer drug sensitivity with several other chemotherapy drugs. Ponatinib was also identified as a cellular inhibitor of necroptosis by inhibiting RIPK1 and RIPK3. It also potently inhibits MEKK2 (IC50 = 10-16nM) and MEKK3 and has been identified as a STAT3 inhibitor.