Quizartinib (AC220) 化学構造
分子量: 560.67

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製品説明

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製品の説明

生物活性

製品説明 Quizartinib (AC220)は、FLT3の強力で選択的な阻害剤で、 FLT3-ITDとFLT3-WT自己リン酸化に作用すると、 IC50がそれぞれ 1.1 nM 、4.2 nMになる。
ターゲット Flt3ITD Flt3wt
IC50 1.1 nM [1] 4.2 nM [1]
In vitro試験 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]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
HL60/VCR NIjTSVNHfW6ldHnvckBCe3OjeR?= MX2wMlEuOTBizszN NVfiT2ZmOzBibXnu NETZXYtmdmijbnPld{B2eHSja3Wgc4Yhe3Wkc4TyZZRmeyCxZjDBRmNIOiCjbnSgRWJESjFiaX6gZUBkd26lZX70doF1cW:wLXTldIVv\GWwdDDtZY5v\XJ? NG\WUHkzOzl4N{G3Oy=>
K562/ABCB1 NYq4b2FHTnWwY4Tpc44hSXO|YYm= NV\1[nFNOC5zLUGwJO69VQ>? NGn2c3Q{OCCvaX6= Mn35[Y5p[W6lZYOgeZB1[WunIH;mJJN2[nO2cnH0[ZMhd2ZiQVLDS|Ih[W6mIFHCR2IyKGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz MoD6NlM6PjdzN{e=
8226/MR20  NI[4VZdHfW6ldHnvckBCe3OjeR?= M4nhU|AvOS1zMDFOwG0> M3\mUFMxKG2rbh?= M{LQ[oVvcGGwY3XzJJVxfGGtZTDv[kB{fWK|dILheIV{KG:oIFHCR2czKGGwZDDBRmNDOSCrbjDhJINwdmOnboTyZZRqd25vZHXw[Y5l\W62IH3hco5meg>? NV\ZZ4hVOjN7NkexO|c>
K562/ABCG2 MmTESpVv[3Srb36gRZN{[Xl? M2TVPFAvOS1zMDFOwG0> MojPN|AhdWmw NYLXfnlk\W6qYX7j[ZMhfXC2YXvlJI9nKHO3YoP0doF1\XNib3[gRWJETzJiYX7kJGFDS0JzIHnuJIEh[2:wY3XueJJifGmxbj3k[ZBmdmSnboSgcYFvdmW{ MVuyN|k3PzF5Nx?=
MCF-7 FLV1000 NUTDboZsU2mwYYPlJGF{e2G7 NVuzU4xiOOLCk{OwJOK2VQ>? Ml7YOUBucW5? M1:zdIRm[3KnYYPld{BcOTJ3SW2tTWFCWCCyaH;0c4xi[mWuaX7nJI9nKEGEQ1KxJIF1KEmFNUCgc4YhOy5|IN88US=> NUTwR|h2OjN7NkexO|c>
MCF-7 FLV1000 NH\UVXlMcW6jc3WgRZN{[Xl? M3\YclDjiJN|MDFCuW0> MY[1JI1qdg>? MXXk[YNz\WG|ZYOgX|EzPUmfLVnBRXAheGixdH;sZYJmdGmwZzDv[kBCSkOEMjDheEBKSzVyIH;mJFAvODdizszN NVjJVoZJOjN7NkexO|c>
K562/ABCG2 NEHDfodE\WyuIG\pZYJqdGm2eTDBd5NigXN? MV:wMlEwOC53L{GgxtVO M{Pl[lk3KGh? MkSwd4Vve2m2aYrld{BMPTZ{L1HCR2czKGOnbHzzJJRwKG2rdH;4ZY51em:wZTD0c5BwfGWlYX9CpC=> Mon6NlM6PjdzN{e=
8226/MR20 MW\D[YxtKF[rYXLpcIl1gSCDc4PhfZM> MmLjNE4yKML3TR?= NHLKd4E6PiCq MXXz[Y5{cXSrenXzJGs2PjJxQVLDS|Ih[2WubIOgeI8hdWm2b4jhcpRzd26nIITvdI91\WOjbtMg NXTxV2dmOjN7NkexO|c>
HMC1.1 MlThS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NFz3bmpKSzVyPUG0JI5O MkTRNlM1QTd|MUe=
HMC1.2 NU\VbmdjT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MmnZTWM2OD1zN{K3JI5O NWDuSHJ[OjN2OUezNVc>
p815 M2Kyc2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFnYfHBKSzVyPUS0OUBvVQ>? Mlu4NlM1QTd|MUe=
Kasumi-1 NULKfWhNT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYrJR|UxRTN4IH7N NUDZNZB1OjN2OUezNVc>
M-07e + SCF M3fiTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NGrnenJKSzVyPUe3JI5O NFPUV2YzOzR7N{OxOy=>
EOL-1 M4PVNmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnPMTWM2OD1zIH7N NHXRcnIzOzR7N{OxOy=>
MV4;11 M2W3dGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NYLmd2ZmUUN3MEygNUBvVQ>? NEW0W4YzOzR7N{OxOy=>
MOLM14 M2rYVmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlS0TWM2ODxiMTDuUS=> M3zTOVI{PDl5M{G3
Pat.221 MoHvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MY\JR|UxRTZ5NTDuUS=> NVyyRo9IOjN2OUezNVc>
Pat.279 M1S2emdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3HxOmlEPTB;M{SzOEBvVQ>? NUTNVYxNOjN2OUezNVc>
Pat.299 NIrxb|NIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYHXSFVOUUN3ME23NlQ5KG6P M4TBV|I{PDl5M{G3
Pat.305 NFTI[2tIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NVHpZoxKUUN3ME23NFc6KG6P NGG2TIMzOzR7N{OxOy=>
Pat.375 MmnKS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MmD6TWM2OD13MEOgcm0> M1[xdlI{PDl5M{G3
Pat.379 NF;v[XNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MY\JR|UxRThyNjDuUS=> MmWwNlM1QTd|MUe=
Pat.368 NVr2eoFVT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M37Ld2lEPTB;MkewNEBvVQ>? NWHFW4RSOjN2OUezNVc>
Pat.601 MmjFS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NWG2NppRUUN3ME2xNVU{KG6P NUDsdZlCOjN2OUezNVc>
HMC1.1 Ml;oRZBweHSxc3nzJGF{e2G7 NVz1[|Q3UUN3ME2zNUBvVQ>? Mn\oNlM1QTd|MUe=
p815 NH60b5JCeG:ydH;zbZMhSXO|YYm= MYfJR|UxRTN2MTDuUS=> NF[1VIgzOzR7N{OxOy=>
Kasumi-1 NVHYcm9TSXCxcITvd4l{KEG|c3H5 M4HMcGlEPTB;Nkegcm0> NGixemszOzR7N{OxOy=>
M-07e + SCF NUXm[IdtSXCxcITvd4l{KEG|c3H5 MmLJTWM2OD15ODDuUS=> NYW2[5VSOjN2OUezNVc>
EOL-1 MlrNRZBweHSxc3nzJGF{e2G7 NWrPUmJtUUN3MEygNUBvVQ>? M3fWflI{PDl5M{G3
MV4;11 NYrkeFJ[SXCxcITvd4l{KEG|c3H5 M{PyXGlEPTB;MjDuUS=> NHLNe2IzOzR7N{OxOy=>
MOLM14 M{\FdmFxd3C2b4Ppd{BCe3OjeR?= NFvjcGVKSzVyPUOgcm0> NXLPbGhvOjN2OUezNVc>
GIST822 MVjBdI9xfG:|aYOgRZN{[Xl? NVvDVHVoUUN3ME2xNFkhdk1? M3XHS|I{PDl5M{G3
Pat.368 MlX3RZBweHSxc3nzJGF{e2G7 MorETWM2OD1{OUm4JI5O NEftcZMzOzR7N{OxOy=>
Pat.601 NWPpcGdSSXCxcITvd4l{KEG|c3H5 NGLYUo5KSzVyPUi3OkBvVQ>? NF\YXZIzOzR7N{OxOy=>
MV4-11 M1nzcWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MlvxO|IhcA>? MlPvTWM2OD1yLkOgcm0> NWXUeXVIOjN2MUK5N|E>
MOLM-14 Mk[4S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M1rKcFczKGh? NGf4UlNKSzVyPUCuNUBvVQ>? NEjMUXczOzRzMkmzNS=>
SEM-K2 NX\HS40xT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MXW3NkBp NYPPT3d{UUN3ME2wMlQhdk1? M4rXO|I{PDF{OUOx
RS4;11 NYPKdFNTT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MoDZO|IhcA>? NF;QPXNKSzVyPkGwMFAxOCCwTR?= NWDvcFNmOjN2MUK5N|E>
THP-1 MYDHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NXWyW4piPzJiaB?= MVjJR|UxRjFyLECwNEBvVQ>? M4[5[|I{PDF{OUOx
MV4-11 NHzmXo5CeG:ydH;zbZMhSXO|YYm= NGrrXYI5NzJ2IHi= MljBbY5lfWOnczDzbYdvcW[rY3HueEBidmRiZH;z[U1l\XCnbnTlcpQhWEGUUDDjcIVifmGpZTDhcoQh[WOldX31cIF1cW:wIH;mJJN2[i1{TjDEUmE> MlnMNlM1OTJ7M{G=
MOLM-14 MlfCRZBweHSxc3nzJGF{e2G7 MUi4M|I1KGh? M1jTT4lv\HWlZYOgd4lodmmoaXPhcpQh[W6mIHTvd4Uu\GWyZX7k[Y51KFCDUmCgZ4xm[X[jZ3WgZY5lKGGlY4XteYxifGmxbjDv[kB{fWJvMl6gSG5C Mmi5NlM1OTJ7M{G=
SEM-K2 MWfBdI9xfG:|aYOgRZN{[Xl? MUW4M|I1KGh? MW\pcoR2[2W|IIPp[45q\mmlYX70JIFv\CCmb4PlMYRmeGWwZHXueEBRSVKSIHPs[YF3[WenIHHu[EBi[2O3bYXsZZRqd25ib3[gd5VjNTKQIFTORS=> NY[0XFc3OjN2MUK5N|E>
MV4-11 NH[1eoZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1nsXlczKGh? NFrwZ2ZKSzVyPUCuOVYhyrFiMD6zJI5O NEHUOYgyQTZ3NESwPC=>
A375 M3fvRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFTYVmU4OiCq NYq3WmVDUUN3ME6gNVAhODByIH7N NGH1cWcyQTZ3NESwPC=>

... Click to View More Cell Line Experimental Data

In vivo試験 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]
臨床試験 A Phase I study of AC220 in patients with relapsed/refractory acute myeloid leukemia, regardless of FLT3 status, has been completed.
特集 The most potent cellular FLT3-ITD inhibitor.

プロトコル (参考用のみ)

キナーゼアッセイ: [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

細胞アッセイ: [1]

細胞株 MV4-11 and RS4;11 cells
濃度 Dissolved in DMSO, final concentration ~20 μM
反応時間 72 hours
実験の流れ 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

動物実験: [1]

動物モデル Female NU/NU or severe combined immunodeficient mice implanted with MV4-11 cells
製剤 Formulated in 22% hydroxypropyl-β-cyclodextrin
投薬量 ~10 mg/kg
投与方法 Oral gavage

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

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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

参考

化学情報

Download Quizartinib (AC220) SDF
分子量 560.67
化学式

C29H32N6O4S

CAS No. 950769-58-1
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 33.2 mg/mL (59.21 mM)
<0.3 mg/mL <0.3
エタノール <0.5 mg/mL <0.5
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.
化学名 Urea, N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-N'-[4-[7-[2-(4-morpholinyl)ethoxy]imidazo[2,1-b]benzothiazol-2-yl]phenyl]-

カスタマーフィードバック (3)


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Rating
Source Mol Cancer Ther, 2014, 13(10), 2315-27. Quizartinib (AC220) purchased from Selleck
Method Western blot
Cell Lines MV4-11 cells
Concentrations 20 uM
Incubation Time 24 h
Results Cotreatment with JQ1 and quizartinib resulted in greater inhibition of the levels of p-STAT5, p-AKT, and p-ERK1/2 without significant alterations in the unphosphorylated versions of these proteins.

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Rating
Source PLoS One, 2013, 8(8), e71266. Quizartinib (AC220) purchased from Selleck
Method Western blot
Cell Lines High-Five insect, MCF-7 FLV1000 cells
Concentrations 0-30 uM
Incubation Time 5 min
Results Since quizartinib inhibited substrate transport by ABCG2 and ABCB1 in a concentration-dependent manner, it sought to confirm that it interacted with established drug-binding sites of these transport proteins. It measured effects of quizartinib on photolabeling of ABCG2 and ABCB1 with [125I]-IAAP. Quizartinib was found to inhibit [125I]-IAAP photolabeling of ABCG2 and ABCB1 with IC50 values of 0.07 礛 and 3.3 礛, respectively.

Click to enlarge
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.

文献中の引用 (12)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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