Ponatinib hydrochloride

AP24534 (Ponatinib) is a reversible, ATP-competitive, BBB-permeable and orally active pan-BCR-ABL inhibitor engineered to overcome multidrug-resistant CML. Its design features a rigid ethynyl linker that bypasses the steric hindrance of the T315I "gatekeeper" mutation, yielding profound potency against native ABL (IC50 0.37 nM), T315I (IC50 2.0 nM), and T315I-inclusive compound mutants (IC50 0.30–0.44 nM). This efficacy extends to cellular models, where it suppresses CrkL phosphorylation and inhibits proliferation in native (IC50 0.5 nM) and T315I-expressing (IC50 11 nM) cells. Beyond ABL, Ponatinib acts as a multi-kinase inhibitor modulating angiogenesis and stromal signaling, with high affinity for LYN (0.24 nM), PDGFRα (1.1 nM), VEGFR2 (1.5 nM), FGFR1-4 (~2.2 nM), SRC (5.4 nM), KIT (~12.5 nM), and FLT3 (~13 nM). Mechanistically, it halts STAT5, ERK, and AKT signaling to trigger cell cycle arrest and intrinsic apoptosis—driven by caspase-3 cleavage and Bcl-xL/Mcl-1 downregulation—or RIPK1/3-mediated necroptosis. To deepen molecular response against complex resistance, Ponatinib demonstrates significant synergy with MDM2 inhibitors, the allosteric inhibitor asciminib, and the BCL-2 inhibitor venetoclax.

Hygroscopic, Store with desiccant