Ponatinib

Specifications / Handling

More Information
Product Details
Synonyms	AP 24534; AP-24534
Product Type	Chemical
Properties
Formula	C₂₉H₂₇F₃N₆O
MW	532.6
CAS	943319-70-8
Purity Chemicals	≥98%
Appearance	Pale yellow solid.
Solubility	Soluble in DMSO (30mg/ml), DMF (30mg/ml) or ethanol (5mg/ml).
InChi Key	PHXJVRSECIGDHY-UHFFFAOYSA-N
Smiles	CC(C=CC(C(NC1=CC(C(F)(F)F)=C(CN2CCN(C)CC2)C=C1)=O)=C3)=C3C#CC4=CN=C5N4N=CC=C5
Shipping and Handling
Shipping	AMBIENT
Short Term Storage	+4°C
Long Term Storage	-20°C
Handling Advice	Keep cool and dry.
Use/Stability	Stable for at least 2 years after receipt when stored at -20°C.
Documents
MSDS	Download PDF
Product Specification Sheet
Datasheet	Download PDF

Product-specific References

Description

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-γ-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 orally bioavailable Bcr-Abl tyrosine kinase inhibitor of native BCR-ABL (IC50 = 0.37nM), the tyrosine kinase inhibitor-resistant mutant Bcr-AblT315I (IC50 = 2nM), as well as Bcr-AblQ252H, Bcr-AblY253F, Bcr-AblM351T and Bcr-AblH396P mutants (IC50s = 0.44, 0.3, 0.3, and 0.34nM, respectively) in biochemical assays. Ponatinib inhibits proliferation of Ba/F3 cells expressing native (IC50 = 0.5nM) or mutant Bcr-Abl (IC50s = 0.5-36nM) and induces apoptosis. It reduces tumor growth in a Ba/F3 Bcr-AblT315I mouse xenograft model when administered at doses ranging from 10 to 30 mg/kg and completely overcame resistance in cell-based mutagenesis screens.
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, 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 PDGFRα, 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. 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).
Ponatinib was 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.
Ponatinib protects against influenza A virus-induced death by suppressing cytokine storm in mouse models and inhibits SARS-CoV-2 replication by non-specific (off-target) effects.

Product References

AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance: T. O'Hare, et al.; Cancer Cell 16, 401 (2009)
Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl) ethynyl]-4-methyl- N-{4-[(4-methylpiperazin-1-yl)methyl]-3 -(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant: W.S. Huang, et al.; J. Med. Chem. 53, 4701 (2010)
Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies: J.M. Gozgit, et al.; Mol. Cancer Ther. 10, 1028 (2011)
Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models: J.M. Gozgit, et al.; Mol. Cancer Ther. 11, 690 (2012)
Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases: E. Lierman, et al.; Leukemia 26, 1693 (2012)
The novel BCR-ABL and FLT3 inhibitor ponatinib is a potent inhibitor of the MDR-associated ATP-binding cassette transporter ABCG2: R. Sen, et al.; Mol. Cancer Ther. 11, 2033 (2012)
Ponatinib (AP24534) is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer: V. De Falco, et al.; J. Clin. Endocrinol. Metab. 98, E811 (2013)
Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase: L. Mologni, et al.; Mol. Cell Endocrinol. 377, 1 (2013)
Ponatinib induces apoptosis in imatinib-resistant human mast cells by dephosphorylating mutant D816V KIT and silencing β-catenin signaling: B. Jin, et al.; Mol. Cancer Ther. 13, 1217 (2014)
A cellular screen identifies ponatinib and pazopanib as inhibitors of necroptosis: A. Fauster, et al.; Cell Death Dis. 6, e1767 (2015)
Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity: S. Ahmad, et al.; BBRC 463, 888 (2015)
Ponatinib: A Third-Generation Inhibitor for the Treatment of CML: J. Wehrle & N. von Bubnoff; Recent Results Cancer Res. 212, 109 (2018)
Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations: J.P. Choi, et al.; Sci. Adv. 4, eaau0731 (2018)
Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth: F.H. Tan, et al.; Cancers 10, 526 (2018)
Ponatinib: a novel multi-tyrosine kinase inhibitor against human malignancies: F.H. Tan, et al.; Onco Targets Ther. 12, 635 (2019) (Review)
Ponatinib Inhibits Proliferation and Induces Apoptosis of Liver Cancer Cells, but Its Efficacy Is Compromised by Its Activation on PDK1/Akt/mTOR Signaling: C. Liu, et al.; Molecules 24, 1363 (2019)
Ponatinib Protects Mice From Lethal Influenza Infection by Suppressing Cytokine Storm: Si. Chen, et al.; Front. Immunol. 10, 1393 (2019)
A Combinatorial Strategy for Targeting BRAF V600E-Mutant Cancers with BRAFV600E Inhibitor (PLX4720) and Tyrosine Kinase Inhibitor (Ponatinib): C. Ghosh, et al.; Clin. Cancer Res. 26, 2022 (2020)
On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2: A. Sauvat, et al.; Cell Death Dis. 11, 656 (2020)

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