950769-58-1|Quizartinib

Quizartinib (AC220) 是一种第二代 Ⅱ 型 FLT3 酪氨酸激酶抑制剂，具有口服活性和高选择性，抑制 FLT3-WT 和 FLT3-ITD 自磷酸化 (IC50=4.1 1.1 nM)。Quizartinib 可以诱导肿瘤细胞凋亡。Quizartinib产品描述：Quizartinib (AC220) is a second-generation type II FLT3 tyrosine kinase inhibitor that is orally active and highly selective, inhibiting the autophosphorylation of FLT3-WT and FLT3-ITD (IC50=4.1/1.1 nM). Quizartinib induces apoptosis in tumor cells.
靶点活性
FLT3:1.6 nM (Kd, cell free)
体外活性：
方法：人白血病细胞系 MV4-11 和人恶性黑色素瘤细胞系 A375 用 Quizartinib 处理 72 h，使用 Cell Titer-Blue Cell Viability Assay 检测细胞活力。
结果：Quizartinib 抑制 MV4-11 细胞生长，IC50 为 0.56  nM。Quizartinib 不影响 A375 细胞的增殖，IC50 大于 10000 nM。[1]
方法：AML 细胞系 MV4-11 用 Quizartinib (0.0625-8 nM) 处理 2 h，使用 Western Blot 检测靶点蛋白表达水平。
结果：Quizartinib 对 MV4-11 细胞中的 FLT3 信号通路具有浓度依赖性抑制活性。Quizartinib 有效抑制 FLT3 磷酸化 (IC50=0.50 nM)。Quizartinib 抑制下游分子 SHP-2、STAT5、MEK1/2、ERK1/2 和 AKT的磷酸化。[2]
体内活性
方法：为检测体内抗肿瘤活性，将 Quizartinib (10 mg/kg，22% hydroxypropyl-β-cyclodextrin, CEP-701 was formulated in 20% gelucire 44/14 in water (vol/vol)) 口服给药给携带 MV4-11 异种移植物的 NU/NU 小鼠，每天一次，持续 28 天。
结果：用 10 mg/kg 的 Quizartinib 治疗导致所有动物的肿瘤快速完全消退，并且在治疗后 60 天的观察期内没有观察到肿瘤再生。[1]
激酶实验
KinomeScan kinase binding assays were performed as previously described. For the FLT3 assay, we used a kinase construct that spanned the catalytic domain only (amino acids 592 to 969 in NP_004110.2). 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].
细胞实验
MV4-11 and RS4;11 cells were cultured in Iscove media with 10% fetal bovine serum (FBS) and RPMI complete with 10% FBS, respectively. For proliferation assays, cells were cultured overnight in low serum media (0.5% FBS), then seeded in a 96-well plate at 40 000 cells per well. Inhibitors were added to the cells and incubated at 37°C for 72 hours. Cell viability was measured using the Cell Titer-Blue Cell Viability Assay. To measure inhibition of FLT3 autophosphorylation, cells were 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 were incubated with inhibitors for 2 hours at 37°C. To induce FLT3 autophosphorylation in RS4;11 cells, 100 ng/mL FLT3 ligand was added for 15 minutes after the 2-hour compound incubation. Cell lysates were prepared and incubated in 96-well plates pre-coated with a total FLT3 capture antibody. The coated plates were 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 was used for electrochemiluminescence detection on the Meso Scale Discovery platform [1].
动物实验
The model was performed according to published procedures.20 For intravenous bone marrow engraftment, nonobese diabetic/severe combined immunodeficient mice were acclimated for 2 weeks before pretreatment with 150 mg/kg cyclophosphamide delivered intraperitoneally once a day for 2 days. After a 48-hour rest period, animals were given an intravenous injection of 5 × 10^6 MV4-11 cells into the tail vein. AC220 was formulated and delivered as described for pharmacokinetic studies [1].
别名 奎扎替x, AC220
化学信息：
分子量：560.67
分子式： C29H32N6O4S
CAS No.： 950769-58-1
Smiles： CC(C)(C)c1cc(NC(=O)Nc2ccc(cc2)-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc32)no1
密度： 1.39 g/cm3 (Predicted)
储存&溶解度：
存储 Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice.
溶解度信息：
DMSO: 16.67 mg/mL (29.73 mM), Sonication is recommended.
Ethanol: < 1 mg/mL (insoluble or slightly soluble)
10% DMSO+40% PEG300+5% Tween 80+45% Saline: 3.32 mg/mL (5.92 mM), suspension.In vivo: Please add the solvents sequentially, clarifying the solution as much as possible before adding the next one. Dissolve by heating and/or sonication if necessary. Working solution is recommended to be prepared and used immediately.
溶液配制表
DMSO
1mg 5mg 10mg 50mg
10 mM 0.1784 mL 0.8918 mL 1.7836 mL 8.9179 mL
20 mM 0.0892 mL 0.4459 mL 0.8918 mL 4.4590 mL
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