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Purity: ≥98%
Quizartinib (formerly also know as AC-220; AC-010220, brand name Vanflyta in Japan; Vanflyta) is a novel, potent, 2nd-generation, and orally bioavailable FLT3 tyrosine kinase inhibitor for Flt3 (ITD/WT) with potential anticancer activity.With IC50s of 1.1 nM and 4.2 nM, respectively, it inhibits FLT3 in MV4-11 and RS4EL11 cells. With respect to KIT, PDGFRα, PDGFRβ, RET, and CSF-1R, it demonstrates a ten-fold greater selectivity. Currently, Daiichi Sankyo is developing quizartinib to treat acute myeloid leukemia. Quizartinib (Vanflyta) was approved in 2023 by FDA for treating AML.
| Targets |
Flt3 (Kd = 1.6±0.7 nM)
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| ln Vitro |
Quizartinib (AC220) is a novel substance designed specifically to inhibit FLT3 in the treatment of acute myeloid leukemia (AML). With an IC50 of 4.2±0.3 nM for FLT3-WT and 1.1±0.1 nM for FLT3-ITD, respectively, quizartinib inhibits FLT3-autophosphorylation. With an IC50 of 0.56±0.3 nM and >10,000 nM, respectively, quizartinib inhibits MV4-11 and A375 cells. When screened against most of the human protein kinome, quizartinib is highly selective and inhibits FLT3 with low nanomolar potency in cellular assays[1].
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| ln Vivo |
Quizartinib (AC220) obliterates tumors in a FLT3-dependent mouse xenograft model at 10 mg/kg, potently inhibits FLT3 activity in primary patient cells, and significantly prolongs survival in a mouse model of FLT3-ITD AML at doses as low as 1 mg/kg when administered orally once daily. When comparing the oral and intravenous pharmacokinetics of quizartinib at 3 mg/kg in rats, the oral bioavailability was found to be roughly 40%. Mice are given a single oral gavage dose of quizartinib at a rate of 10 mg/kg, and they are killed twice after the dose in groups of four animals each. Time-dependent inhibition of FLT3 autophosphorylation was found in tumor samples when total FLT3 and phospho-FLT3 were quantified. After administration, FLT3 activity is reduced by 90% after two hours and 40% after twenty-four hours. Therefore, based on pharmacokinetic experiments, the degree of inhibition correlated favorably with the anticipated free Quizartinib plasma levels[1].
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| Enzyme Assay |
Kinase binding experiments using KinomeScan are conducted. The kinase construct used in the FLT3 assay spanned only the catalytic domain (amino acids 592 to 969). The juxtamembrane domain is absent from this construct, which is intended to quantify the intrinsic binding affinity of inhibitors to the open FLT3 active site[1].
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| Cell Assay |
The cells MV4-11 and RS4;11 are cultivated in Iscove media supplemented with 10% fetal bovine serum (FBS) and RPMI complete with 10% FBS, respectively. In order to perform proliferation assays, cells are seeded at a density of 40,000 cells per well in a 96-well plate after being cultured for an entire night in low serum media (0.5% FBS). The cells are supplemented with inhibitors (such as quizartinib) and incubated for 72 hours at 37°C. The Cell Titer-Blue Cell Viability Assay is used to measure cell viability. Cells are cultured in low serum medium (0.5% FBS) overnight, and the next day, they are seeded at a density of 400 000 cells per well in a 96-well plate to measure the inhibition of FLT3 autophosphorylation. Inhibitors, such as quizartinib, are cultured in the cells for two hours at 37°C. The 2-hour compound incubation is followed by a 15-minute addition of 100 ng/mL FLT3 ligand to cause FLT3 autophosphorylation in RS4;11 cells. Prepared cell lysates are incubated in 96-well plates that have been coated with a total FLT3 capture antibody beforehand. Either a biotinylated FLT3 antibody or an anti-phosphotyrosine antibody is used to incubate on the coated plates in order to detect total FLT3 or FLT3 autophosphorylation. For electrochemiluminescence detection on the Meso Scale Discovery platform, a SULFO-tagged streptavidin secondary antibody is utilized in both situations[1].
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| Animal Protocol |
Mice: The mice used are female nu/NU or severe combined immunodeficient mice. Quizartinib (hydrochloride salt) is formulated in 22% hydroxypropyl-β-cyclodextrin, CEP-701 is formulated in 20% gelucire 44/14 in water (vol/vol), MLN-518 and SU 11248 are formulated in 10 mM sodium citrate (pH 3.5), PKC-412 is formulated in 3:1 gelucire 44/14-propylene glycol (vol/vol), and Bay 43-9006 is formulated in 80% PEG-400. Compound concentrations are selected in a volume of 10 mL/kg to deliver the intended dose. Oral gavage is used to administer compounds, and plasma samples are taken 0,25,0.5,1,2,4,6, and 24 hours after dosing. In order to obtain three independent plasma concentration time courses, eye bleeds (150 μL) are obtained semilongitudinally using three groups of three animals each, taking two to three time points per animal. Using four volumes of acetonitrile containing an internal standard, plasma samples and controls (25 μL) are extracted, and liquid chromatography tandem mass spectrometry is used for analysis.
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| References |
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| Molecular Formula |
C29H32N6O4S
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|---|---|
| Molecular Weight |
560.67
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| Exact Mass |
560.22
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| Elemental Analysis |
C, 62.13; H, 5.75; N, 14.99; O, 11.41; S, 5.72
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| CAS # |
950769-58-1
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| Related CAS # |
1132827-21-4 (HCl);950769-58-1;
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| Appearance |
Solid powder
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| SMILES |
CC(C)(C)C1=CC(=NO1)NC(=O)NC2=CC=C(C=C2)C3=CN4C5=C(C=C(C=C5)OCCN6CCOCC6)SC4=N3
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| InChi Key |
CVWXJKQAOSCOAB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H32N6O4S/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36)
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| Chemical Name |
1-(5-tert-butyl-1,2-oxazol-3-yl)-3-[4-[6-(2-morpholin-4-ylethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl]urea
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| Synonyms |
Quizartinib; AC220 or AC010220; AC 220; AC-220; AC-010220; AC 010220;Vanflyta
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7836 mL | 8.9179 mL | 17.8358 mL | |
| 5 mM | 0.3567 mL | 1.7836 mL | 3.5672 mL | |
| 10 mM | 0.1784 mL | 0.8918 mL | 1.7836 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02668653 | Active Recruiting |
Drug: Quizartinib Drug: Placebo |
Leukemia Acute Myeloid Leukemia |
Daiichi Sankyo, Inc. | September 2016 | Phase 3 |
| NCT04107727 | Active Recruiting |
Drug: Quizartinib Drug: Cytarabine |
Acute Myeloid Leukemia | PETHEMA Foundation | September 5, 2019 | Phase 2 |
| NCT04493138 | Recruiting | Drug: Quizartinib Drug: Azacitidine |
Myelodysplastic Syndrome Myeloproliferative Neoplasm |
M.D. Anderson Cancer Center | July 21, 2020 | Phase 1 Phase 2 |
| NCT04128748 | Recruiting | Drug: Quizartinib Drug: Liposome-encapsulated Daunorubicin-Cytarabine |
Acute Myeloid Leukemia High Risk Myelodysplastic Syndrome |
M.D. Anderson Cancer Center | May 27, 2020 | Phase 1 Phase 2 |
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