Ponatinib (AP24534) is an orally active multi-targeted kinase inhibitor withIC₅₀s of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM, and 5.4 nM forAbl,PDGFRα,VEGFR2,FGFR1, andSrc, 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 IC₅₀values of 13, 13, 2, and 1 nM, respectively. Ponatinib inhibits phosphorylation of all 4 RTKs in a dose-dependent manner, with IC₅₀values 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 IC₅₀values of 0.5 to 17 nM. In contrast, the IC₅₀for inhibition of RS4;11 cells which express native (unmutated) FLT3, is more than 100 nM^[2].

In a survival model in which mice are instead injected with Ba/F3 BCR-ABL^T315Icells, 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^T315Icells 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].

532.56

Solid

C₂₉H₂₇F₃N₆O

943319-70-8

帕纳替尼；帕拉替尼；泊那替尼；普纳替尼

Room temperature in continental US; may vary elsewhere.

1M HCl : 50 mg/mL(93.89 mM;ultrasonic and adjust pH to 1 with HCl)

DMSO : 50 mg/mL(93.89 mM;Need ultrasonic)

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80℃, 6 months; -20℃, 1 month。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。

请根据您的实验动物和给药方式选择适当的溶解方案。以下溶解方案都请先按照In Vitro方式配制澄清的储备液，再依次添加助溶剂：

——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议您现用现配，当天使用； 以下溶剂前显示的百
分比是指该溶剂在您配制终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

• 1.

  请依序添加每种溶剂： 10% DMSO    40%PEG300   5%Tween-80   45% saline

  Solubility: ≥ 2.5 mg/mL (4.69 mM); Clear solution

  此方案可获得 ≥ 2.5 mg/mL (4.69 mM，饱和度未知) 的澄清溶液。

  以 1 mL 工作液为例，取 100 μL 25.0 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀；向上述体系中加入50 μL Tween-80，混合均匀；然后继续加入 450 μL生理盐水定容至 1 mL。

  将 0.9 g 氯化钠，完全溶解于 100 mL ddH2O 中，得到澄清透明的生理盐水溶液