Ponatinib  (Synonyms: AP24534)

Ponatinib (AP24534) is an orally active multi-targeted kinase inhibitor with IC₅₀s 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^[1].

Ponatinib (AP24534) potently inhibits native ABL (IC₅₀: 0.37 nM), ABL^T315I (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-ABL^T315I (IC₅₀: 11 nM)^[1].
Ponatinib 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].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

In a survival model in which mice are instead injected with Ba/F3 BCR-ABL^T315I 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-ABL^T315I 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].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

532.56

C₂₉H₂₇F₃N₆O

943319-70-8

Solid

Light yellow to yellow

CC1=C(C=C(C=C1)C(NC2=CC(C(F)(F)F)=C(C=C2)CN3CCN(CC3)C)=O)C#CC4=CN=C5N4N=CC=C5

Room temperature in continental US; may vary elsewhere.

* Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 2 years; -20°C, 1 year. When stored at -80°C, please use it within 2 years. When stored at -20°C, please use it within 1 year.

• [1]. O'Hare T, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell, 2009, 16(5), 401-412.  [Content Brief]

  [2]. Gozgit JM, et al. Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther, 2011, 10(6), 1028-1035.  [Content Brief]

  [3]. Uchida T, et al. Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis. Exp Hematol. 2014 May;42(5):369-379.e3.  [Content Brief]