Quizartinib (AC220)

Quizartinib (AC220)は一種の第二代FLT3阻害剤で、MV4-11と RS411細胞にFlt3(ITD/WT)に作用する時のIC50値が1.1 nM/4.2 nMです。Quizartinib (AC220)は、Flt3に作用する選択性はKIT、PDGFRA、PDGFRB、RETとCSF-1Rに作用する選択性より10倍が高くなります。臨床3期。

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Quizartinib (AC220) 化学構造
分子量: 560.67

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製品説明

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    FLT3製品生物活性の比較
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製品の説明

生物活性

製品説明 Quizartinib (AC220)は一種の第二代FLT3阻害剤で、MV4-11と RS411細胞にFlt3(ITD/WT)に作用する時のIC50値が1.1 nM/4.2 nMです。Quizartinib (AC220)は、Flt3に作用する選択性はKIT、PDGFRA、PDGFRB、RETとCSF-1Rに作用する選択性より10倍が高くなります。臨床3期。
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 NXTxOmZWTnWwY4Tpc44hSXO|YYm= MlPMNE4yNTFyIN88US=> MXizNEBucW5? Mnnk[Y5p[W6lZYOgeZB1[WunIH;mJJN2[nO2cnH0[ZMhd2ZiQVLDS|Ih[W6mIFHCR2IyKGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NXP4SVFjOjN7NkexO|c>
K562/ABCB1 NWnoNXJMTnWwY4Tpc44hSXO|YYm= MVSwMlEuOTBizszN Mk[wN|AhdWmw Mlvx[Y5p[W6lZYOgeZB1[WunIH;mJJN2[nO2cnH0[ZMhd2ZiQVLDS|Ih[W6mIFHCR2IyKGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz M1voUVI{QTZ5MUe3
8226/MR20  NFPYV5pHfW6ldHnvckBCe3OjeR?= M3;YU|AvOS1zMDFOwG0> Ml7tN|AhdWmw MlTk[Y5p[W6lZYOgeZB1[WunIH;mJJN2[nO2cnH0[ZMhd2ZiQVLDS|Ih[W6mIFHCR2IyKGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NUPtb3NYOjN7NkexO|c>
K562/ABCG2 MkjrSpVv[3Srb36gRZN{[Xl? MXKwMlEuOTBizszN Mny1N|AhdWmw MlfV[Y5p[W6lZYOgeZB1[WunIH;mJJN2[nO2cnH0[ZMhd2ZiQVLDS|Ih[W6mIFHCR2IyKGmwIHGgZ49v[2WwdILheIlwdi2mZYDlcoRmdnRibXHucoVz NWm0OW9WOjN7NkexO|c>
MCF-7 FLV1000 MX7LbY5ie2ViQYPzZZk> NEnNV4Qx6oDVM{CgxtVO MkPvOUBucW5? MlTp[IVkemWjc3XzJHsyOjWLXT3JRWFRKHCqb4TvcIFj\Wyrbnegc4YhSUKFQkGgZZQhUUN3MDDv[kA{NjNizszN NHK0bFAzOzl4N{G3Oy=>
MCF-7 FLV1000 NGfJN5VMcW6jc3WgRZN{[Xl? M3[1c|DjiJN|MDFCuW0> NYq5XlhmPSCvaX6= MoHV[IVkemWjc3XzJHsyOjWLXT3JRWFRKHCqb4TvcIFj\Wyrbnegc4YhSUKFQkKgZZQhUUN3MDDv[kAxNjB5IN88US=> MmrSNlM6PjdzN{e=
K562/ABCG2 NU\GdG5uS2WubDDWbYFjcWyrdImgRZN{[Xm| M{PjdFAvOS9yLkWvNUDDvU1? NVvxU3pIQTZiaB?= NXvwV|R{e2Wwc3n0bZpmeyCNNU[yM2FDS0d{IHPlcIx{KHSxIH3peI95[W62cn;u[UB1d3CxdHXjZY7DqA>? MmHaNlM6PjdzN{e=
8226/MR20 MVvD[YxtKF[rYXLpcIl1gSCDc4PhfZM> MYiwMlEhyrWP MlzSPVYhcA>? MmLSd4Vve2m2aYrld{BMPTZ{L1HCR2czKGOnbHzzJJRwKG2rdH;4ZY51em:wZTD0c5BwfGWlYX9CpC=> MUKyN|k3PzF5Nx?=
HMC1.1 M{XhZWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4H5TGlEPTB;MUSgcm0> MmXWNlM1QTd|MUe=
HMC1.2 NXLscYxUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NF;5Z4FKSzVyPUG3Nlchdk1? MonYNlM1QTd|MUe=
p815 M2HTTWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MX7JR|UxRTR2NTDuUS=> MVqyN|Q6PzNzNx?=
Kasumi-1 NHTNbohIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NW\v[o03UUN3ME2zOkBvVQ>? MVWyN|Q6PzNzNx?=
M-07e + SCF M3\yT2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NF;xUWlKSzVyPUe3JI5O M3\WZVI{PDl5M{G3
EOL-1 NHzG[pBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MWPJR|UxRTFibl2= MkT2NlM1QTd|MUe=
MV4;11 MUfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MWrJR|UxRCBzIH7N MlzFNlM1QTd|MUe=
MOLM14 MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoDSTWM2ODxiMTDuUS=> Mmn1NlM1QTd|MUe=
Pat.221 MYPHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NF;vVpFKSzVyPU[3OUBvVQ>? NWHtbIhNOjN2OUezNVc>
Pat.279 MmT2S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXvJR|UxRTN2M{Sgcm0> MYOyN|Q6PzNzNx?=
Pat.299 MXzHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NVTJ[YlwUUN3ME23NlQ5KG6P M4qzNlI{PDl5M{G3
Pat.305 M{jZO2dzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWG3cJdpUUN3ME23NFc6KG6P MX:yN|Q6PzNzNx?=
Pat.375 NFPBcoZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MlK5TWM2OD13MEOgcm0> MorXNlM1QTd|MUe=
Pat.379 MVfHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NHvofmpKSzVyPUiwOkBvVQ>? NELZZ|EzOzR7N{OxOy=>
Pat.368 NGD5SlZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MVPJR|UxRTJ5MECgcm0> MXqyN|Q6PzNzNx?=
Pat.601 Mnn0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NGToXIVKSzVyPUGxOVMhdk1? MknZNlM1QTd|MUe=
HMC1.1 MUfBdI9xfG:|aYOgRZN{[Xl? MnLpTWM2OD1|MTDuUS=> MYOyN|Q6PzNzNx?=
p815 MXjBdI9xfG:|aYOgRZN{[Xl? M{PSN2lEPTB;M{SxJI5O MWKyN|Q6PzNzNx?=
Kasumi-1 MmLSRZBweHSxc3nzJGF{e2G7 MVvJR|UxRTZ5IH7N NGDQRYgzOzR7N{OxOy=>
M-07e + SCF M4LVdWFxd3C2b4Ppd{BCe3OjeR?= NWHWWG83UUN3ME23PEBvVQ>? M1vYd|I{PDl5M{G3
EOL-1 MVTBdI9xfG:|aYOgRZN{[Xl? Mk[5TWM2ODxiMTDuUS=> NEXxe4czOzR7N{OxOy=>
MV4;11 Ml7QRZBweHSxc3nzJGF{e2G7 M{TIOWlEPTB;MjDuUS=> M4LxTlI{PDl5M{G3
MOLM14 MXvBdI9xfG:|aYOgRZN{[Xl? NIfO[WtKSzVyPUOgcm0> NHnJNZczOzR7N{OxOy=>
GIST822 M3r5UGFxd3C2b4Ppd{BCe3OjeR?= M1;IbWlEPTB;MUC5JI5O MY[yN|Q6PzNzNx?=
Pat.368 M{PtXGFxd3C2b4Ppd{BCe3OjeR?= MkDPTWM2OD1{OUm4JI5O NFrSVnIzOzR7N{OxOy=>
Pat.601 M{jJ[WFxd3C2b4Ppd{BCe3OjeR?= MmDJTWM2OD16N{[gcm0> NY\qXm5qOjN2OUezNVc>
MV4-11 Mk\aS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUTGRpg3PzJiaB?= NEjNcWhKSzVyPUCuN{BvVQ>? M2nPcVI{PDF{OUOx
MOLM-14 NEHHOHRIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MoPXO|IhcA>? M1jLV2lEPTB;MD6xJI5O M32zRVI{PDF{OUOx
SEM-K2 NFHaRotIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M4LOW|czKGh? Ml3wTWM2OD1yLkSgcm0> M3GzVlI{PDF{OUOx
RS4;11 M3nLXmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MnPiO|IhcA>? M2flXGlEPTB-MUCsNFAxKG6P MV[yN|QyOjl|MR?=
THP-1 MkXuS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NX3F[nNRPzJiaB?= M2\udGlEPTB-MUCsNFAxKG6P NEDx[Y8zOzRzMkmzNS=>
MV4-11 MVLBdI9xfG:|aYOgRZN{[Xl? NHn3NYg5NzJ2IHi= MWjpcoR2[2W|IIPp[45q\mmlYX70JIFv\CCmb4PlMYRmeGWwZHXueEBRSVKSIHPs[YF3[WenIHHu[EBi[2O3bYXsZZRqd25ib3[gd5VjNTKQIFTORS=> NETYSJEzOzRzMkmzNS=>
MOLM-14 NVzqW4dySXCxcITvd4l{KEG|c3H5 NH\reYE5NzJ2IHi= M1;pTolv\HWlZYOgd4lodmmoaXPhcpQh[W6mIHTvd4Uu\GWyZX7k[Y51KFCDUmCgZ4xm[X[jZ3WgZY5lKGGlY4XteYxifGmxbjDv[kB{fWJvMl6gSG5C MWGyN|QyOjl|MR?=
SEM-K2 MlzJRZBweHSxc3nzJGF{e2G7 NFm2NmM5NzJ2IHi= MXrpcoR2[2W|IIPp[45q\mmlYX70JIFv\CCmb4PlMYRmeGWwZHXueEBRSVKSIHPs[YF3[WenIHHu[EBi[2O3bYXsZZRqd25ib3[gd5VjNTKQIFTORS=> MVSyN|QyOjl|MR?=
MV4-11 NYTVTHc1T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M37T[VczKGh? NFzQcWFKSzVyPUCuOVYhyrFiMD6zJI5O MnzNNVk3PTR2MEi=
A375 NEjVfVNIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= Ml3OO|IhcA>? MnTlTWM2OD5iMUCgNFAxKG6P MoHjNVk3PTR2MEi=

... 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 3年-20℃
2年-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 33.2 mg/mL (59.21 mM)
Water <0.3 mg/mL <0.3
Ethanol <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]-

文献中の引用 (13)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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