Ponatinib (hydrochloride)

Ponatinib is an orally bioavailable Bcr-Abl tyrosine kinase inhibitor (IC₅₀ = 0.37 nM).¹ It inhibits the tyrosine kinase inhibitor-resistant mutant Bcr-Abl^T315I (IC₅₀ = 2 nM), as well as Bcr-Abl^Q252H, Bcr-Abl^Y253F, Bcr-Abl^M351T, and Bcr-Abl^H396P mutants (IC₅₀s = 0.44, 0.3, 0.3, and 0.34 nM, respectively). It is selective for Bcr-Abl and these mutants over the insulin receptor, IGF-1R, Aurora A kinase, and Cdk2/cyclin E but does inhibit the receptor tyrosine kinases c-Src, VEGF receptor 2 (VEGFR2), FGFR1, and PDGFRα (IC₅₀s = 5.4, 1.5, 2.2, and 1.1 nM, respectively). Ponatinib inhibits proliferation of Ba/F3 cells expressing native (IC₅₀ = 0.5 nM) or mutant Bcr-Abl (IC₅₀s = 0.5-36 nM) and induces apoptosis. It reduces tumor growth in a Ba/F3 Bcr-Abl^T315I mouse xenograft model when administered at doses ranging from 10 to 30 mg/kg. Formulations containing ponatinib have been used in the treatment of chronic-, accelerated-, or blast-phase chronic myeloid leukemia (CML), T315I-positive CML, or T315I-positive Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

1.O’Hare, T., Shakespeare, W.C., Zhu, X., et al.AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistanceCancer Cell16(5)401-412(2009)