Desmorpholinyl Quizartinib-PEG2-COOH

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Desmorpholinyl Quizartinib-PEG2-COOH  纯度: 95.09%

Desmorpholinyl Quizartinib-PEG2-COOH 包含靶蛋白 FLT-3 配体和一种基于 PEG 的 PROTAC Linker。Desmorpholinyl Quizartinib-PEG2-COOH 可用于合成 PROTAC FLT-3 degrader 1 (HY-114323)。PROTAC FLT-3 degrader 1 是 PROTAC FLT-3 ITD 降解剂,IC50 为 0.6 nM。

Desmorpholinyl Quizartinib-PEG2-COOH

Desmorpholinyl Quizartinib-PEG2-COOH Chemical Structure

CAS No. : 2292116-14-2

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生物活性

Desmorpholinyl Quizartinib-PEG2-COOH incorporates a ligand for FLT-3, and a PEG-based PROTAC linker. Desmorpholinyl Quizartinib-PEG2-COOH can be used in the synthesis of PROTAC FLT-3 degrader 1 (HY-114323). PROTAC FLT-3 degrader 1 is a PROTAC FLT-3 internal tandem duplication (ITD) degrader with an IC50 0.6 nM[1].

分子量

607.68

Formula

C30H33N5O7S

CAS 号

2292116-14-2

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
参考文献
  • [1]. Burslem GM, et al. Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion. J Am Chem Soc. 2018 Dec 5;140(48):16428-16432.

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Quizartinib(Synonyms: 奎扎替尼; AC220)

上海金畔生物科技有限公司为生命科学和医药研发人员提供生物活性分子抑制剂、激动剂、特异性抑制剂、化合物库、重组蛋白,专注于信号通路和疾病研究领域。

Quizartinib (Synonyms: 奎扎替尼; AC220) 纯度: 98.87%

Quizartinib (AC220) 是一种具有口服活性的、高选择性的,有效的第二代 Ⅱ 型 FLT3 (type II FLT3) 酪氨酸激酶抑制剂,Kd 值为 1.6 nM。Quizartinib 抑制 Wt FLT3 和 突变型 FLT3-ITD 自磷酸化,IC50 分别为 4.1 nM 和 1.1 nM。Quizartinib 可以通过优化的 linker 与 VHL 配体连接,从而形成 PROTAC Flt3 降解剂。Quizartinib 诱导细胞凋亡 (apoptosis)。

Quizartinib(Synonyms: 奎扎替尼; AC220)

Quizartinib Chemical Structure

CAS No. : 950769-58-1

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10 mM * 1 mL in DMSO ¥1172 In-stock
5 mg ¥950 In-stock
10 mg ¥1550 In-stock
50 mg ¥4200 In-stock
100 mg ¥7200 In-stock
200 mg ¥9950 In-stock
500 mg ¥19500 In-stock
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生物活性

Quizartinib (AC220) is an orally active, highly selective and potent second-generation type II FLT3 tyrosine kinase inhibitor, with a Kd of 1.6 nM. Quizartinib inhibits wild-type FLT3 and FLT3-ITD autophosphorylation in MV4-11 cells with IC50s of 4.2 and 1.1 nM, respectively. Quizartinib can be linked to the VHL ligand via an optimized linker to form a PROTAC FLT3 degrader. Quizartinib induces apoptosis[1].

IC50 & Target

Kd: 1.6±0.7 nM (Flt3)[1]

体外研究
(In Vitro)

Quizartinib (AC220) is a novel compound expressly optimized as a FLT3 inhibitor for the treatment of acute myeloid leukemia (AML). Quizartinib inhibits FLT3-WT and FLT3-ITD autophosphorylation with IC50 of 4.2±0.3 nM and 1.1±0.1 nM, respectively. Quizartinib inhibits MV4-11 and A375 cells with IC50 of 0.56±0.3 nM and >10 000 nM, respectively. Quizartinib inhibits FLT3 with low nanomolar potency in cellular assays and is highly selective when screened against the majority of the human protein kinome[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

体内研究
(In Vivo)

Quizartinib (AC220) inhibits FLT3 activity in vivo, significantly extends survival in a mouse model of FLT3-ITD AML at doses as low as 1 mg/kg when dosed orally once a day, eradicates tumors in a FLT3-dependent mouse xenograft model at 10 mg/kg, and potently inhibits FLT3 activity in primary patient cells. The oral bioavailability of Quizartinib, determined in rats by comparing oral and intravenous pharmacokinetics at 3 mg/kg, is approximately 40%. A single 10 mg/kg dose of Quizartinib is administered by oral gavage, and mice are killed at 2 time points after dosing, using groups of 4 animals each. Quantitation of total FLT3 and phospho-FLT3 in tumor samples revealed time-dependent inhibition of FLT3 autophosphorylation. FLT3 activity is inhibited by 90% at 2 hours, and 40% at 24 hours after administration. The extent of inhibition therefore correlated well with the expected free Quizartinib plasma levels, based on pharmacokinetic experiments[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial

分子量

560.67

Formula

C29H32N6O4S

CAS 号

950769-58-1

中文名称

奎扎替尼

运输条件

Room temperature in continental US; may vary elsewhere.

储存方式
Powder -20°C 3 years
4°C 2 years
In solvent -80°C 6 months
-20°C 1 month
溶解性数据
In Vitro: 

DMSO : ≥ 33 mg/mL (58.86 mM)

* “≥” means soluble, but saturation unknown.

配制储备液
浓度 溶剂体积 质量 1 mg 5 mg 10 mg
1 mM 1.7836 mL 8.9179 mL 17.8358 mL
5 mM 0.3567 mL 1.7836 mL 3.5672 mL
10 mM 0.1784 mL 0.8918 mL 1.7836 mL

*

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液;一旦配成溶液,请分装保存,避免反复冻融造成的产品失效
储备液的保存方式和期限:-80°C, 6 months; -20°C, 1 month。-80°C 储存时,请在 6 个月内使用,-20°C 储存时,请在 1 个月内使用。

In Vivo:
  • 1.

    Quizartinib (AC220) is prepared in vehicle (22% hydroxypropyl-β-cyclodextrin in sterile water)[2].

参考文献
  • [1]. Zarrinkar PP, 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]. Puissant A, et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell. 2014 Feb 10;25(2):226-42.

    [3]. Sun X, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019 Dec 24;4:64.

Kinase Assay
[1]

KinomeScan kinase binding assays are performed. For the FLT3 assay, a kinase construct that spanned the catalytic domain only (amino acids 592 to 969) is used. This construct does not include the juxtamembrane domain and is designed to measure the intrinsic binding affinity of the open FLT3 active site for inhibitors[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

MV4-11 and RS4;11 cells are cultured in Iscove media with 10% fetal bovine serum (FBS) and RPMI complete with 10% FBS, respectively. For proliferation assays, cells are cultured overnight in low serum media (0.5% FBS), then seeded in a 96-well plate at 40 000 cells per well. Inhibitors (e.g., Quizartinib) are added to the cells and incubated at 37°C for 72 hours. Cell viability is measured using the Cell Titer-Blue Cell Viability Assay. To measure inhibition of FLT3 autophosphorylation, 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 inhibitors (e.g., Quizartinib) 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 compound 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[1].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[1]

Mice[1]
Female NU/NU or severe combined immunodeficient mice are used. Quizartinib (hydrochloride salt) is formulated in 22% hydroxypropyl-β-cyclodextrin, CEP-701 is formulated in 20% gelucire 44/14 in water (vol/vol), MLN-518 and SU 11248 are formulated in 10 mM sodium citrate (pH 3.5), PKC-412 is formulated in 3:1 gelucire 44/14-propylene glycol (vol/vol), and Bay 43-9006 is formulated in 80% PEG-400. Compound concentrations are chosen to deliver the desired dose in a volume of 10 mL/kg. Compounds are administered by oral gavage and plasma samples collected 0.25, 0.5, 1, 2, 4, 6, and 24 hours after dosing. To collect plasma samples, eye bleeds (150 μL) are taken semilongitudinally using 3 groups of 3 animals each, taking 2 to 3 time points per animal to obtain a total of 3 independent plasma concentration time courses. Plasma samples and controls (25 μL) are extracted with 4 volumes of acetonitrile containing an internal standard and analyzed by liquid chromatography tandem mass spectrometry.

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

参考文献
  • [1]. Zarrinkar PP, 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]. Puissant A, et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell. 2014 Feb 10;25(2):226-42.

    [3]. Sun X, et al. PROTACs: great opportunities for academia and industry. Signal Transduct Target Ther. 2019 Dec 24;4:64.

所有产品仅用作科学研究或药证申报,我们不为任何个人用途提供产品和服务