Quizartinib (AC220)

Quizartinib (AC220) is a second-generation FLT3 inhibitor for Flt3(ITD/WT) with IC50 of 1.1 nM/4.2 nM, 10-fold more selective for Flt3 than KIT, PDGFRα, PDGFRβ, RET, and CSF-1R. Phase 3.

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Quizartinib (AC220) Chemical Structure

Quizartinib (AC220) Chemical Structure
Molecular Weight: 560.67

Validation & Quality Control

Customer Reviews(1)

Quality Control & MSDS

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Quizartinib (AC220) is available in the following compound libraries:

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Product Description

Biological Activity

Description Quizartinib (AC220) is a second-generation FLT3 inhibitor for Flt3(ITD/WT) with IC50 of 1.1 nM/4.2 nM, 10-fold more selective for Flt3 than KIT, PDGFRα, PDGFRβ, RET, and CSF-1R. Phase 3.
Targets FLT3 (ITD) [1] FLT3 (WT) [1]
IC50 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(Only for 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
Formulation Formulated in 22% hydroxypropyl-β-cyclodextrin
Dosages ~10 mg/kg
Administration Oral gavage
Solubility 15% Captisol, , 30 mg/mL
* 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.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Zarrinkar PP, et al. Blood, 2009, 114(14), 2984-2992.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2014-09-13)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02039726 Recruiting AML Ambit Biosciences Corporation April 2014 Phase 3
NCT01892371 Recruiting Leukemia M.D. Anderson Cancer Center|Ambit Biosciences Corporation|Celgene Corporation November 2013 Phase 1|Phase 2
NCT01565668 Active, not recruiting Leukemia, Myeloid, Acute Ambit Biosciences Corporation April 2012 Phase 2
NCT01468467 Active, not recruiting Leukemia, Myeloid, Acute, Ambit Biosciences Corporation April 2012 Phase 1
NCT01576185 Recruiting Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Childrens Oncology Group|National Cancer Institute (NCI) April 2012 --

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Chemical Information

Download Quizartinib (AC220) SDF
Molecular Weight (MW) 560.67
Formula

C29H32N6O4S

CAS No. 950769-58-1
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 33.2 mg/mL (59 mM)
Water <0.3 mg/mL
Ethanol <0.5 mg/mL
In vivo 15% Captisol, 30 mg/mL
* <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.
Chemical Name Urea, N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-N'-[4-[7-[2-(4-morpholinyl)ethoxy]imidazo[2,1-b]benzothiazol-2-yl]phenyl]-

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Customer Reviews (1)


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Rating
Source Quizartinib (AC220) purchased from Selleck
Method MTT Assay
Cell Lines epidermoid carcinoma cell line
Concentrations 0.75-3 μM
Incubation Time
Results Effect of AC220 on the sensitivity of KB-C2 cells to paclitaxel.

Product Citations (11)

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