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Quizartinib (AC220)

现货
Catalog No.
A5793
FLT3抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 700.00
现货
5mg
¥ 550.00
现货
25mg
¥ 1,650.00
现货
100mg
¥ 4,200.00
现货

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Background

Quizartinib (AC220) is a 2nd-generation FLT3 inhibitor for Flt3(ITD/WT) with IC50 value of 1.1 nM/4.2 nM, and it is ten-fold more selective for Flt3 than PDGFRα, PDGFRβ, KIT, RET and CSF-1R [1].

Quizartinib inhibits FLT3 with low nanomolar potency in cellular assays and shows high selectivity when screened against most of the human protein kinome. In addition, the combination of high potency and selectivity exhibited by quizartinib is unique compared with CEP-701, PKC-412, MLN-518, sunitinib, and sorafenib.

Quizartinib (AC220) was identified to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties and superior efficacy in tumor xenograft models. A single dose of 10 mg/kg was administered to mice by oral gavage and plasma levels were measured over a 24-hour period. Quizartinib was well absorbed, achieving a maximum plasma level (Cmax) of 3.8 μM (2100 ng/mL) within 2 hours of dosing. To determine the effect of FLT3-ITD inhibition on cell growth,. These results establish that AC220 has strong activity against FLT3 in biochemical and cellular assays in MV4-11 cell proliferation in the presence of 1.1nM quizartinib [1].

As a FLT3 inhibitor for the treatment of acute myeloid leukemia (AML), when at doses as low as 1 mg/kg orally once a day, quizartinib inhibits FLT3 activity in vivo extending survival significantly. And this eradicates tumors in a FLT3-dependent mouse xenograft model, and potently inhibits FLT3 activity in primary patient cells at a dose of 10 mg/kg. In addition, quizartinib has been demonstrated a desirable safety and PK profile in humans. The emergence of resistant mutations is a common mechanism of resistance to FLT3 inhibitors used clinically, with a mutation emerging in at least 20% of the patients. This shows that the survival of AML blasts depends to a great extent on FLT3 signaling in these cases [2, 3].

References:
[1].  Zarrinkar PP, Gunawardane RN, Cramer MD, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood, 2009, 114(14): 2984-2992.
[2]. Chao Q, Sprankle KG, Grotzfeld RM, et al. Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor. Journal of Medicinal Chemistry, 2009, 52(23): 7808-7816.
[3].  Alvarado Y , Kantarjian HM, Luthra R, et al. Treatment With FLT3 Inhibitor in Patients With FLT3-Mutated Acute Myeloid Leukemia Is Associated With Development of Secondary FLT3-Tyrosine Kinase Domain Mutations. Cancer, 2014, 120(14): 2142-2149.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt560.67
Cas No.950769-58-1
FormulaC29H32N6O4S
Solubility≥28.0335mg/mL in DMSO, <2.05 mg/mL in EtOH, <2.44 mg/mL in H2O
Chemical Name1-(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
SDFDownload SDF
Canonical SMILESCC(C)(C)C1=CC(=NO1)NC(=O)NC2=CC=C(C=C2)C3=CN4C5=C(C=C(C=C5)OCCN6CCOCC6)SC4=N3
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

激酶实验 [1]:

FLT3自磷酸化抑制实验

为了测定FLT3自磷酸化,将MV4-11细胞或RS4;11细胞置于低血清培养基 (0.5% FBS) 培养过夜。于第2天,以每孔400 000个细胞的密度将细胞接种于96孔板上。在37 °C下,将细胞与不同浓度的AC220孵育2小时。为了诱导RS4;11细胞FLT3自磷酸化,于孵育2小时后,加入100 ng/mL FLT3配体。在包被了FLT3抗体的96孔板中,制备并孵育细胞裂解物。加入抗FLT3的生物素化抗体以测定FLT3总量,或加入磷酸酪氨酸抗体以测定FLT3自磷酸化。在上述两种情况下,使用Meso Scale Discovery平台检测电化学发光(SULFO标签链霉亲和素二抗)。AC220抑制50% FLT3-ITD或TLT3-WT自磷酸化的浓度为IC50值。

细胞实验 [1]:

细胞系

MV4-11细胞或RS4;11细胞

制备方法

在DMSO中的溶解度大于10 mM。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20 °C可放置数月。

反应条件

20 μM;72小时

实验结果

在MV4-11细胞或RS4;11细胞中,AC220抑制FLT3自磷酸化,其IC50值分别为1.1 nM和4.2 nM。

动物实验 [1]:

动物模型

携带MV4-11肿瘤的小鼠

给药剂量

10 mg/kg;口服给药

实验结果

在携带MV4-11肿瘤的小鼠中,AC220呈时间依赖性地抑制FLT3自磷酸化。

其它注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1]. Zarrinkar PP, Gunawardane RN, Cramer MD, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood, 2009, 114(14): 2984-2992.

生物活性

描述 Quizartinib (AC220)是第二代FLT3抑制剂,作用于Flt3(ITD/WT),IC50值为1.1 nM/4.2 nM,对Flt3的选择性比对KIT、PDGFRα、PDGFRβ、RET和CSF-1R高10倍。
靶点 Flt3ITD Flt3wt        
IC50 1.1 nM 4.2 nM        

质量控制

化学结构

Quizartinib (AC220)

相关生物数据

Quizartinib (AC220)

相关生物数据

Quizartinib (AC220)