| 名稱 | Quizartinib |
| 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. |
| 細(xì)胞實驗 | 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]. |
| 激酶實驗 | 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]. |
| 動物實驗 | 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]. |
| 體外活性 | 方法：人白血病細(xì)胞系 MV4-11 和人惡性黑色素瘤細(xì)胞系 A375 用 Quizartinib 處理 72 h，使用 Cell Titer-Blue Cell Viability Assay 檢測細(xì)胞活力。
結(jié)果：Quizartinib 抑制 MV4-11 細(xì)胞生長，IC50 為 0.56 ?nM。Quizartinib 不影響 A375 細(xì)胞的增殖，IC50 大于 10000 nM。[1]
方法：AML 細(xì)胞系 MV4-11 用 Quizartinib (0.0625-8 nM) 處理 2 h，使用 Western Blot 檢測靶點蛋白表達(dá)水平。
結(jié)果：Quizartinib 對 MV4-11 細(xì)胞中的 FLT3 信號通路具有濃度依賴性抑制活性。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] |
| 體內(nèi)活性 | 方法：為檢測體內(nèi)抗腫瘤活性，將 Quizartinib (10 mg/kg，22% hydroxypropyl-β-cyclodextrin, CEP-701 was formulated in 20% gelucire 44/14 in water (vol/vol)) 口服給藥給攜帶 MV4-11 異種移植物的 NU/NU 小鼠，每天一次，持續(xù) 28 天。
結(jié)果：用 10 mg/kg 的 Quizartinib 治療導(dǎo)致所有動物的腫瘤快速完全消退，并且在治療后 60 天的觀察期內(nèi)沒有觀察到腫瘤再生。[1] |
| 存儲條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | 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. Please add co-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.
|
| 關(guān)鍵字 | AC-220 | Inhibitor | myeloid | FLT3-ITD | Apoptosis | oral | Autophagy | Fms like tyrosine kinase 3 | Target Protein-binding Moiety | mutation | inhibit | Quizartinib | CD135 | AML | leukemia | Ligands for Target Protein for PROTAC | acute | AC 220 | Cluster of differentiation antigen 135 | FLT3 | selective |
| 相關(guān)產(chǎn)品 | Guanidine hydrochloride | Naringin | Valproic Acid | L-Glutamic acid | Gefitinib | Hydroxychloroquine | Dextran sulfate sodium salt (MW 4500-5500) | Stavudine | Tributyrin | L-Ascorbic acid | Paeonol | Sodium 4-phenylbutyrate |
| 相關(guān)庫 | 抗癌上市藥物庫 | 經(jīng)典已知活性庫 | 已知活性化合物庫 | EMA 上市藥物庫 | 抗衰老化合物庫 | 酪氨酸激酶分子庫 | 抗癌藥物庫 |