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Osimertinib mesylate (AZD-9291 mesylate) is a third-generation EGFR inhibitor, shows similar potency to early generation tyrosine kinase inhibitor (TKIs) in inhibiting EGFR phosphorylation in EGFR cells harboring sensitising EGFR mutants including PC-9 (ex19del), H3255 (L858R) and H1650 (ex19del), with mean IC50 values ranging from 13 to 54 nM for Osimertinib. Osimertinib (AZD-9291) also potently inhibits phosphorylation of EGFR in T790M mutant cell lines (H1975 (L858R/T790M), PC-9VanR (ex19del/T790M), with mean IC50 potency less than 15 nM.
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Source | Mol Pharm (2016). Figure 2.AZD-9291 |
| Method | immunoblotting | |
| Cell Lines | cancer cell lines | |
| Concentrations | 0.1 - 1 μM | |
| Incubation Time | 72 h | |
| Results | Cells were maintained in the absence or presence of increasing concentrations (0.1 - 1 μM) of osimertinib for 72 h, harvested and processed for immunoblotting as described in Materials and methods. |
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Source | Mol Pharm (2016). Figure 1.AZD-9291 |
| Method | flow cytometry | |
| Cell Lines | MDR19-HEK293 cells | |
| Concentrations | 10 μM | |
| Incubation Time | 24 h | |
| Results | Osimertinib (10 μM) significantly increased the accumulation of fluorescent calcein, an established substrate of ABCB145 in ABCB1-overexpressing KB-V-1 cells and ABCB1-transfected MDR19-HEK293 cells to the same extent as tariquidar, a known inhibitor of ABCB1 |
| Cell Experiment | |
|---|---|
| Cell lines | PC-9 cells |
| Preparation method | Media changes are carried out every 2-3 days and resistant clones allowed to grow to 80% confluency prior to the cells being trypsinised and reseeded at the original seeding density in media containing twice the concentration of EGFR inhibitor. Dose escalations are continued until a final concentration of 1.5 μM Gefitinib, 1.5 μM Afatinib, 1.5 μM WZ4002 or 160 nM AZD-9291 are achieved. |
| Concentrations | 160 nM |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | Mice |
| Formulation | 1% Polysorbate 80 |
| Dosages | 7.5 mg/kg and 5 mg/kg |
| Administration | oral |
| Molecular Weight | 595.71 |
| Formula | C29H37N7O5S |
| CAS Number | 1421373-66-1 |
| Solubility (25°C) | DMSO 9 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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