Ponatinib (AP24534) is a novel potent BCR-ABL or BCR-ABLT3151 with an IC50 values of 0.37 and 2.0 nM, respectively. Ponatinib (AP24534) also inhibits other ABL kinase domain mutants at nanomolar potencies. AP24534 exhibits inhibitory activity against PDGFRα, c-Src and c-Kit (IC50 values are 1.1, 5.4 and 12.5 nM respectively) potently inhibits FGFR and VEGFR family kinases.
J Virol. 2020 Feb 14;94(5):e01791-19.
Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use
AP24534 purchased from AbMole
Transl Stroke Res. 2017 Nov 4.
Combination of Emricasan with Ponatinib Synergistically Reduces Ischemia/Reperfusion Injury in Rat Brain Through Simultaneous Prevention of Apoptosis and Necroptosis
AP24534 purchased from AbMole
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Source | Transl Stroke Res. (2017). Figure 7. Ponatinib (Abmole Bioscience, China) |
| Method | i.g. | |
| Cell Lines | rat | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 24 h | |
| Results | Compared with sham group, the protein expressions of RIPK1, RIPK3, andMLKL in the rat brains were up-regulated in the I/R group, which were suppressed by ponatinib alone or combination with emricasan, whereas emricasan alone had no effect on the expressions of RIPK1, RIPK3, and MLKL (Fig. 7). |
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Source | Transl Stroke Res. (2017). Figure 6. Ponatinib (Abmole Bioscience, China) |
| Method | i.g. | |
| Cell Lines | rat | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 24 h | |
| Results | Compared with the sham group, there were significant increases in the caspase-3 and caspase-8 activities in the I/R-treated rat brains; these increases were obviously blocked in the presence of emricasan alone or together with ponatinib, whereas ponatinib alone did not affect the caspase-3 and caspase-8 activities (Fig. 6). |
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Source | Transl Stroke Res. (2017). Figure 5. Ponatinib (Abmole Bioscience, China) |
| Method | i.g. | |
| Cell Lines | rat | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 24 h | |
| Results | As displayed in Fig. 5, consistent with the results before, emricasan or ponatinib alone could reduce the neurological deficit score and infarct volume in the I/R-treated rats; these effects were obviously enhanced upon the combined application of emricasan and ponatinib. |
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Source | Transl Stroke Res. (2017). Figure 4. Ponatinib (Abmole Bioscience, China) |
| Method | i.g. | |
| Cell Lines | rat | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 24 h | |
| Results | As shown in Fig. 4, the neurological deficit score and infarct volume were obviously decreased in the presence of emricasan (A and B) or ponatinib (C and D) compared to that in the I/R group, whereas the vehicle of emricasan or ponatinib has no such effects. |
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Source | Transl Stroke Res. (2017). Figure 3. Ponatinib (Abmole Bioscience, China) |
| Method | i.g. | |
| Cell Lines | rat | |
| Concentrations | 20 mg/kg | |
| Incubation Time | 24 h | |
| Results | Cerebral I/R caused dramatic increases in neurological deficit score and infarct volume; these increases were attenuated by pretreatment with emricasan (A and B) or ponatinib (C and D), whereas the vehicle of emricasan or ponatinib did not show such effects. |
| Cell Experiment | |
|---|---|
| Cell lines | MV4-11, Kasumi-1, KG1, and EOL1 cells |
| Preparation method | Cell viability assays. Cell viability was assessed using the Cell Titer 96 Aqueous One Solution Cell Proliferation Assay. Exponentially growing cell lines were plated into 96-well plates and incubated overnight at 37°C. Twenty-four hours after plating, cells were treated with compound or vehicle (dimethyl sulfoxide) for 72 hours. Absorbance was measured using a Wallac Victor microplate reader (PerkinElmer). Data are plotted as percent viability relative to vehicle-treated cells and the IC50 values (the concentration that causes 50% inhibition) are calculated using XLfit version 4.2.2 for Microsoft Excel. Data are shown as mean (±SD) from 3 separate experiments, each tested in triplicate. |
| Concentrations | 0~100 nM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | MV4-11 human tumor subcutaneous xenograft model |
| Formulation | aqueous 25 mmol/L citrate buffer (pH = 2.75) |
| Dosages | 1, 2.5, 5, 10, and 25 mg/kg/d once daily for 4 weeks |
| Administration | orally |
| Molecular Weight | 532.56 |
| Formula | C29H27F3N6O |
| CAS Number | 943319-70-8 |
| Solubility (25°C) | DMSO ≥ 40 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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