Ponatinib (hydrochloride)

Ponatinib is a multi-kinase inhibitor.^1,2 It inhibits Bcr-Abl (IC₅₀ = 0.37 nM), the tyrosine kinase inhibitor-resistant mutant Bcr-Abl^T315I (IC₅₀ = 2 nM), and various other Bcr-Abl mutants (IC₅₀s = 0.3-0.44 nM).¹ It is selective for Bcr-Abl and these mutants over the insulin receptor, IGF-1R, Aurora A kinase, and Cdk2/cyclin E (IC₅₀s = >1,000 nM for all) but does inhibit c-Src, VEGFR2, FGFR1, and PDGFRα (IC₅₀s = 5.4, 1.5, 2.2, and 1.1 nM, respectively). Ponatinib also inhibits RIPK2 (IC₅₀ = 6.7 nM) and reduces NOD2-mediated RIPK2 ubiquitination in THP-1 cells and NF-κB activation in a reporter assay in vitro.² Ponatinib inhibits activation of the NLRP3 inflammasome in mouse bone marrow-derived macrophages (BMDMs) at 1 µM and reduces IL-1β secretion from primary mouse microglia at 0.5 µM without affecting cell viability.³ It also induces apoptosis in Ba/F3 cells expressing Bcr-Abl or mutant Bcr-Abl and reduces tumor growth in a Ba/F3 Bcr-Abl^T315I mouse xenograft model at 10-30 mg/kg.¹ Formulations containing ponatinib have been used in the treatment of leukemia.

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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 resistance. Cancer Cell 16(5), 401-412 (2009).

2. Canning, P., Ruan, Q., Schwerd, T., et al. Inflammatory signaling by NOD-RIPK2 is inhibited by clinically relevant type II kinase inhibitors. Chem. Biol. 22(9), 1174-1184 (2015).

3. Evered, A.H., Shippy, D.C., Lash, J.N., et al. The anti-leukemia drug ponatinib attenuates NLRP3 inflammasome activation in macrophages. Immunobiology 231(5), 153241 (2026).