1. Protein Tyrosine Kinase/RTK
    Autophagy
  2. Bcr-Abl
    PDGFR
    VEGFR
    FGFR
    Src
    Autophagy

Ponatinib (Synonyms: AP24534)

Cat. No.: HY-12047 Purity: 98.96%
Data Sheet SDS Handling Instructions

Ponatinib is a potent, orally available multi-targeted kinase inhibitor with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM, and 5.4 nM for Abl, PDGFRα, VEGFR2, FGFR1, and Src, respectively.

For research use only. We do not sell to patients.
Ponatinib Chemical Structure

Ponatinib Chemical Structure

CAS No. : 943319-70-8

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Customer Review

    Ponatinib purchased from MCE. Usage Cited in: Exp Hematol. 2014 May;42(5):369-379.e3.

    (B,D) Phosphorylation levels of F/P (or its mutant), STAT5, or ERK in lysates of CMPs expressing Hes1 with F/P, F/P-D842V, or F/P-T674I, which have been treated with indicated doses of (B) Imatinib or (D) Ponatinib for 15 min. Data are representative of three independent experiments.
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    Ponatinib is a potent, orally available multi-targeted kinase inhibitor with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM, and 5.4 nM for Abl, PDGFRα, VEGFR2, FGFR1, and Src, respectively.

    IC50 & Target

    IC50: 0.37 nM (Abl), 0.24 nM (Lyn), 1.1 nM (PDGFRα), 1.5 nM (VEGFR2), 2.2 nM (FGFR1), 5.4 nM (Src)[1]

    In Vitro

    Ponatinib (AP24534) potently inhibits native ABL (IC50: 0.37 nM), ABLT315I (IC50: 2.0 nM), and other clinically important ABL kinase domain mutants (IC50: 0.30-0.44 nM). Ponatinib also inhibits SRC (IC50: 5.4 nM) and members of the VEGFR, FGFR, and PDGFR families of receptor tyrosine kinases. Ponatinib potently inhibits proliferation of Ba/F3 cells expressing native BCR-ABL (IC50: 0.5 nM). All BCR-ABL mutants tested remained sensitive to Ponatinib (IC50: 0.5-36 nM) including BCR-ABLT315I (IC50: 11 nM)[1]. Ponatinib (AP24534) inhibits the in vitro kinase activity of FLT3, KIT, FGFR1, and PDGFRα with IC50 values of 13, 13, 2, and 1 nM, respectively. Ponatinib inhibits phosphorylation of all 4 RTKs in a dose-dependent manner, with IC50 values between 0.3 to 20 nM. Consistent with these activated receptors being important in driving leukemogenesis Ponatinib also potently inhibits the viability of all 4 cell lines with IC50 values of 0.5 to 17 nM. In contrast, the IC50 for inhibition of RS4;11 cells which express native (unmutated) FLT3, is more than 100 nM[2].

    In Vivo

    In a survival model in which mice are instead injected with Ba/F3 BCR-ABLT315I cells, administration of Dasatinib at doses as high as 300 mg/kg has no effect on survival time. By contrast, treatment with Ponatinib (AP24534) prolongs survival in a dose-dependent manner. Ponatinib dosed orally for 19 days at 5, 15, and 25 mg/kg prolongs median survival to 19.5, 26, and 30 days, respectively compare to 16 days for vehicle-treated mice (p<0.01 for all three dose levels). The anti-tumor activity of Ponatinib (AP24534) is further assessed in a xenograft model in which Ba/F3 BCR-ABLT315I cells are injected subcutaneously into mice. Tumor growth is inhibited by Ponatinib in a dose-dependent manner compare to vehicle-treated mice, with significant suppression of tumor growth upon daily oral dosing at 10 and 30 mg/kg (%T/C = 68% and 20%, respectively; p<0.01 for both dose levels). Daily oral dosing of 50 mg/kg Ponatinib causes significant tumor regression (%T/C = 0.9%, p<0.01), with a 96% reduction in mean tumor volume at the final measurement compared to the start of treatment. Ponatinib is well tolerated at all efficacious dose levels for the duration of the study; maximal decreases in body weight are <5%, <5%, and <12% for the 10, 30, and 50 mg/kg dose groups, respectively, with no signs of overt toxicity[1]. Ponatinib (1-25 mg/kg) is administered orally, once daily for 28 days, to mice bearing MV4-11 xenografts. Ponatinib potently inhibits tumor growth in a dose-dependent manner. Administration of 1 mg/kg, the lowest dose tested, leads to significant inhibition of tumor growth (TGI=46%, P<0.01) and doses of 2.5 mg/kg or greater results in tumor regression[2].

    Clinical Trial
    NCT Number Sponsor Condition Start Date Phase
    NCT02428543 Versailles Hospital Acute Myeloid Lukemia July 2013 Phase 1|Phase 2
    NCT01746836 M.D. Anderson Cancer Center|Ariad Pharmaceuticals Leukemia January 2013 Phase 2
    NCT01761747 Dana-Farber Cancer Institute Non-Small Cell Lung Cancer, Head and Neck Cancer January 2013 Phase 2|Phase 3
    NCT01888562 Washington University School of Medicine Endometrial Neoplasms January 2016
    NCT01592136 Ariad Pharmaceuticals Chronic Myeloid Leukemia (CML)|Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
    NCT01935336 University of Colorado, Denver|Ariad Pharmaceuticals Adenocarcinoma of the Lung|Extensive Stage Small Cell Lung Cancer|Limited Stage Small Cell Lung Cancer|Recurrent Non-small Cell Lung Cancer|Recurrent Small Cell Lung Cancer|Stage IIIA Non-small Cell Lung Cancer|Stage IIIB Non-small Cell Lung Cancer|Stage IV Non-small Cell Lung Cancer May 21, 2014 Phase 2
    NCT01570868 M.D. Anderson Cancer Center|Ariad Pharmaceuticals Leukemia April 2012 Phase 2
    NCT01667133 Ariad Pharmaceuticals Chronic Myeloid Leukemia (CML)|Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) August 2012 Phase 1|Phase 2
    NCT02478164 Dana-Farber Cancer Institute Glioblastoma July 2015 Phase 2
    NCT02627677 Ariad Pharmaceuticals Chronic Phase Chronic Myeloid Leukemia December 2015 Phase 3
    NCT01813734 Massachusetts General Hospital Non Small Cell Lung Cancer September 2013 Phase 2
    NCT01549548 OHSU Knight Cancer Institute|Ariad Pharmaceuticals Philadelphia Chromosome Positive (Ph+) Leukemias|Chronic Myeloid Leukemia
    NCT02398825 Gruppo Italiano Malattie EMatologiche dell'Adulto Chronic Myeloid Leukemia|Chronic Phase|Adults August 2016 Phase 2
    NCT02272998 Sameek Roychowdhury|Ohio State University Comprehensive Cancer Center Malignant Neoplasm February 2015 Phase 2
    NCT01207440 Ariad Pharmaceuticals Chronic Myeloid Leukemia|Ph+ Acute Lymphoblastic Leukemia September 2010 Phase 2
    NCT01641107 Gruppo Italiano Malattie EMatologiche dell'Adulto Philadelphia Positive|BCR-ABL Positive|Acute Lymphoblastic Leukemia October 2014 Phase 2
    NCT02829840 M.D. Anderson Cancer Center|Ariad Pharmaceuticals Leukemia|FLT3-Mutated Acute Myeloid Leukemia|FLT3-Mutated High-Risk Myelodysplastic Syndrome September 2016 Phase 1|Phase 2
    NCT02467270 Ariad Pharmaceuticals Myeloid Leukemia, Chronic, Chronic Phase June 2015 Phase 2
    NCT02265341 Mayo Clinic|National Cancer Institute (NCI) Malignant Hepatobiliary Neoplasm December 2014 Phase 2
    NCT01874665 Ariad Pharmaceuticals GIST June 2013 Phase 2
    NCT03171389 Sebastian Bauer|Hannover Medical School|Helios Klinikum Berlin|University Hospital Tuebingen|Universitätsmedizin Mannheim|University Hospital, Aachen|Helios Klinikum Bad Saarow|WiSP GmbH|Universität Duisburg-Essen GIST, Malignant|KIT Exon 13 Mutation|KIT Gene Mutation March 22, 2017 Phase 2
    NCT01838642 National Institutes of Health Clinical Center (CC)|National Cancer Institute (NCI) Thyroid Neoplasms March 2013 Phase 2
    NCT02981784 Hospices Civils de Lyon Leukemia January 2000
    NCT00660920 Ariad Pharmaceuticals Chronic Myelogenous Leukemia|Hematologic Malignancies June 2008 Phase 1
    NCT01650805 Ariad Pharmaceuticals Chronic Myeloid Leukemia June 2012 Phase 3
    NCT02776605 PETHEMA Foundation ALL June 2016 Phase 2
    NCT01424982 M.D. Anderson Cancer Center|Ariad Pharmaceuticals Leukemia October 2011 Phase 2
    NCT03147612 M.D. Anderson Cancer Center|Ariad Pharmaceuticals Acute Lymphoblastic Leukemia August 2017 Phase 2
    NCT02448095 Gruppo Italiano Malattie EMatologiche dell'Adulto Chronic Myeloid Leukemia|Philadelphia Positive December 2015
    NCT01620216 OHSU Knight Cancer Institute|National Cancer Institute (NCI) Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome|Chronic Myelomonocytic Leukemia|Myelodysplastic Syndrome|Recurrent Adult Acute Lymphoblastic Leukemia|Recurrent Adult Acute Myeloid Leukemia|Refractory Adult Acute Lymphoblastic Leukemia May 2012 Phase 2
    NCT02779283 OHSU Knight Cancer Institute|National Cancer Institute (NCI) Untreated Adult Acute Myeloid Leukemia December 2015 Phase 1
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    References
    Preparing Stock Solutions
    Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
    1 mM 1.8777 mL 9.3886 mL 18.7772 mL
    5 mM 0.3755 mL 1.8777 mL 3.7554 mL
    10 mM 0.1878 mL 0.9389 mL 1.8777 mL
    Cell Assay
    [1]

    Ponatinib (AP24534) is dissolved in DMSO (10 mM) and stored (−20°C), and then diluted with appropriate media before use[1].

    Ba/F3 cell lines are distributed in 96-well plates (4×103 cells/well) and incubated with escalating concentrations of Ponatinib for 72 hr. The inhibitor ranges used are: 0-625 nM for cells expressing BCR-ABL and 0-10,000 nM for BCR-ABL negative cells. Proliferation is measured using a methanethiosulfonate (MTS)-based viability assay. IC50 values are reported as the mean of three independent experiments performed in quadruplicate. For cell proliferation experiments with CML or normal primary cells, mononuclear cells are plated in 96-well plates (5×104 cells/well) over graded concentrations of Ponatinib (0-1000 nM) in RPMI supplemented with 10% FBS, L-glutamine, penicillin/streptomycin, and 100 μM β-mercaptoethanol. Following a 72 hr incubation, cell viability is assessed by subjecting cells to an MTS assay[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    Ponatinib (AP24534) is prepared in 25 mM citrate buffer (pH 2.75) (Mice)[1].

    Mice[1]
    For Ba/F3 survival model, Ba/F3 cells expressing native BCR-ABL or BCR-ABLT315I are injected into the tail vein of female SCID mice (100 μL of a 1×107 cells/mL suspension in serum-free medium). Beginning 72 hr later mice are treated once daily by oral gavage with vehicle (25 mM citrate buffer, pH 2.75), Ponatinib, or Dasatinib for up to 19 consecutive days. Moribund animals are sacrificed as per IACUC guidelines. On necropsy, mice have marked splenomegaly due to tumor cell infiltration. Survival data are analyzed using Kaplan-Meier method, and statistical significance is evaluated with a Log-rank test comparing the survival time of each treatment group with the vehicle group. For Ba/F3 Tumor Model, Ba/F3 BCR-ABLT315I cells are implanted subcutaneously into the right flank of female nude mice (100 μL of a 1×107 cells/mL cell suspension in serum-free medium). Mice are randomized to treatment groups when the average tumor volume reaches approximately 500 mm3. Mice are treated once daily by oral gavage with vehicle (25 mM citrate buffer, pH 2.75) or Ponatinib for up to 19 consecutive days. Tumor volume (mm3) is calculated. To determine tumor growth inhibition when the treatment period is finished, mean tumor volume for treatment group/mean tumor volume for control group (%T/C) is calculated at the final measurement. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    532.56

    Formula

    C₂₉H₂₇F₃N₆O

    CAS No.

    943319-70-8

    Storage

    Please store the product under the recommended conditions in the Certificate of Analysis.

    Shipping

    Room temperature in continental US; may vary elsewhere

    Solvent & Solubility

    DMSO: ≥ 50 mg/mL

    Ponatinib is prepared in citrate buffer (pH 2.75)[3].

    * "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

    References

    Purity: 98.96%

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    Ponatinib
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