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Quizartinib (AC220) is a orally-administered, potent and selective inhibitor of two receptor tyrosine kinases, FLT3 and KIT. Quizartinib (AC220) exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. While other agents showed some ability to clear leukemia from the circulating blood, AC220 has shown significant ability to clear leukemic cells from the bone marrow, where the disease originates. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.
Drug Des Devel Ther. 2018 Apr 30;12:1009-1017.
Advances in the drug therapies of acute myeloid leukemia (except acute promyelocytic leukemia)
Quizartinib (AC220) purchased from AbMole
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Source | Mol Cancer (2013). Figure 3. AC220 |
| Method | PCR | |
| Cell Lines | Ba/F3 cells | |
| Concentrations | 0 – 5000 nM | |
| Incubation Time | 48 h | |
| Results | Comparison of inhibition of cellular proliferation after quizartinib treatment revealed strong correlation between naturally occurring and engineered cell lines expressing identical mutant kinases |
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Source | Mol Cancer (2013). Figure 2. AC220 |
| Method | cell apoptosis assay | |
| Cell Lines | leukemia cell line | |
| Concentrations | 0 – 5000 nM | |
| Incubation Time | 48 h | |
| Results | This finding suggests that the distinct mutant-KIT isoform directly orchestrates sensitivity towards quizartinib. |
| Cell Experiment | |
|---|---|
| Cell lines | MV4-11 and RS4;11 cells |
| Preparation method | Cellular assays. MV4-11 and RS4;11 cells were cultured in Iscove media with 10% fetal bovine serum (FBS) and RPMI complete with 10% FBS, respectively. For proliferation assays, cells were cultured overnight in low serum media (0.5% FBS), then seeded in a 96-well plate at 40 000 cells per well. Inhibitors were added to the cells and incubated at 37°C for 72 hours. Cell viability was measured using the Cell Titer-Blue Cell Viability Assay from Promega. To measure inhibition of FLT3 autophosphorylation, cells were cultured in low serum media (0.5% FBS) overnight and seeded at a density of 400 000 cells per well in a 96-well plate the following day. The cells were incubated with inhibitors for 2 hours at 37°C. To induce FLT3 autophosphorylation in RS4;11 cells, 100 ng/mL FLT3 ligand (R&D Systems) was added for 15 minutes after the 2-hour compound incubation. Cell lysates were prepared and incubated in 96-well plates precoated with a total FLT3 capture antibody (R&D Systems). The coated plates were incubated with either a biotinylated antibody against FLT3 (R&D Systems) to detect total FLT3 or an antibody against phosphotyrosines (Millipore) to detect FLT3 autophosphorylation. In both cases, a SULFO-tagged streptavidin secondary antibody was used for electrochemiluminescence detection on the Meso Scale Discovery platform. |
| Concentrations | 0~10 µM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | subcutaneous tumor model |
| Formulation | 22% hydroxypropyl-β-cyclodextrin |
| Dosages | 10 mg/kg |
| Administration | orally |
| Molecular Weight | 560.67 |
| Formula | C29H32N6O4S |
| CAS Number | 950769-58-1 |
| Solubility (25°C) | DMSO ≥100 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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