Quizartinib (AC220)

Catalog No.S1526 Batch:S152601

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Technical Data

Formula

C29H32N6O4S
Molecular Weight 560.67 CAS No. 950769-58-1
Solubility (25°C)* In vitro DMSO 33.2 mg/mL (59.21 mM)
Water Insoluble
Ethanol Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Quizartinib (AC220) is a second-generation FLT3 inhibitor for Flt3(ITD/WT) with IC50 of 1.1 nM/4.2 nM in MV4-11 and RS4;11 cells, respectively, 10-fold more selective for Flt3 than KIT, PDGFRα, PDGFRβ, RET, and CSF-1R. Quizartinib (AC220) induces apoptosis of tumor cells. Phase 3.
Targets
FLT3 (ITD) [1]
(MV4-11 cells)		 FLT3 (WT) [1]
(RS4;11 cells)
1.1 nM 4.2 nM
In vitro AC220, a unique, potent and selective inhibitor of FLT3, has high affinity for FLT3 with a Kd value of 1.6 nM. AC220 inhibits the autophosphorylation of FLT3 in the human leukemia cell lines MV4-11 which harbor a homozygous FLT3-ITD mutation and is FLT3 dependent, and RS4;11 which expresses wild-type FLT3 with IC50 values of 1.1 nM and 4.2 nM, respectively. AC220 is the most potent cellular FLT3-ITD inhibitor, leading to the most significant inhibition of MV4-11 cell proliferation with IC50 of 0.56 nM compared to all other FLT3 inhibitors whose IC50 values range from 0.87 nM to 64 nM. AC220 has no inhibitory activity against the proliferation of A375 cells which harbor an activating mutation in BRAF and are not FLT3 dependent, indicating a large window between FLT3 inhibition and general cytotoxic effects. [1]
In vivo Oral administration of AC220 (10 mg/kg) induces time-dependent inhibition of FLT3 autophosphorylation in the FLT3-ITD–dependent MV4-11 tumor xenograft mouse model; the inhibition being 90% at 2 hours and 40% at 24 hours. AC220 significantly extends survival in a mouse model of FLT3-ITD AML with doses as low as 1 mg/kg given orally once a day. Treatment with AC220 at 10 mg/kg for 28 days results in rapid and complete regression of tumors in all mice with no tumor regrowth during the 60-day posttreatment period. AC220 displays more significant efficacy compared to sunitinib treatment which causes tumors to shrink slowly and resume growth immediately upon discontinuation of treatment in all but one of the mice. [1]
Features The most potent cellular FLT3-ITD inhibitor.

Protocol (from reference)

Kinase Assay:[1]
  • Inhibition of FLT3 autophosphorylation

    To measure inhibition of FLT3 autophosphorylation, MV4-11 or RS4;11 cells are 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 are incubated with different concentrations of AC220 for 2 hours at 37 °C. To induce FLT3 autophosphorylation in RS4;11 cells, 100 ng/mL FLT3 ligand is added for 15 minutes after the 2-hour AC220 incubation. Cell lysates are prepared and incubated in 96-well plates precoated with a total FLT3 capture antibody. The coated plates are incubated with either a biotinylated antibody against FLT3 to detect total FLT3 or an antibody against phosphotyrosines to detect FLT3 autophosphorylation. In both cases, a SULFO-tagged streptavidin secondary antibody is used for electrochemiluminescence detection on the Meso Scale Discovery platform. The concentration of AC220 that inhibits FLT3-ITD or TLT3-WT autophosphorylation by 50% represents IC50 value
Cell Assay:[1]
  • Cell lines

    MV4-11 and RS4;11 cells

  • Concentrations

    Dissolved in DMSO, final concentration ~20 μM

  • Incubation Time

    72 hours

  • Method

    Cells are cultured overnight in low serum media (0.5% FBS), seeded in a 96-well plate at 40 000 cells per well and exposed to AC220 for 72 hours at 37 °C. Cell viability is measured using the Cell Titer-Blue Cell Viability Assa
Animal Study:[1]
  • Animal Models

    Female NU/NU or severe combined immunodeficient mice implanted with MV4-11 cells

  • Dosages

    ~10 mg/kg

  • Administration

    Oral gavage

Customer Product Validation

Data from [Data independently produced by Mol Cancer Ther, 2014, 13(10), 2315-27]

Data from [Data independently produced by PLoS One, 2013, 8(8), e71266]

, , Leuk Lymphoma, 2017, 58(10):2426-2438

,

Selleck's Quizartinib (AC220) has been cited by 145 publications

Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket [ Cell, 2024, S0092-8674(24)00908-5] PubMed: 39255801
Mapping the proteogenomic landscape enables prediction of drug response in acute myeloid leukemia [ Cell Rep Med, 2024, 5(1):101359] PubMed: 38232702
Targeting FLT3-TAZ signaling to suppress drug resistance in blast phase chronic myeloid leukemia [ Mol Cancer, 2023, 10.1186/s12943-023-01837-4] PubMed: 37932786
Targeting FLT3 with a new-generation antibody-drug conjugate in combination with kinase inhibitors for treatment of AML [ Blood, 2023, 141(9):1023-1035] PubMed: 35981498
A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment [ Cell Rep Med, 2023, 10.1016/j.xcrm.2023.101286] PubMed: 37951217
Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth [ Cell Rep, 2023, 42(12):113568] PubMed: 38104314
Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation [ JCI Insight, 2023, 8(17)e168445] PubMed: 37681415
Structural and functional analyses of a germline KRAS T50I mutation provide insights into Raf activation [ JCI Insight, 2023, 8(17)e168445] PubMed: 37681415
The Flt3-inhibitor quizartinib augments apoptosis and promotes maladaptive remodeling after myocardial infarction in mice [ Apoptosis, 2023, 10.1007/s10495-023-01911-8] PubMed: 37945814
The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors [ Cell Death Discov, 2023, 9(1):44] PubMed: 36739272

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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