产品介绍９/div>
基本信息
| 分子弎/td> |
C22H27FN4O2C4H6O5 |
| 分子野/td> |
532.56 |
| 熔点 |
185-192 |
| 折光?n20D) |
1.61 |
| MDL编码 |
MFCD08282795 |
产品描述
Sunitinib Malate是一种多靶点RTK抑制剂，作用于VEGFR2 (Flk-1) PDGFR，在无细胞试验中IC50分别?0 nM ? nM，也会抑制c-Kit的活性、/p>
靶点（IC50 & Targe（/b>
FGFR1,2.9M
PDGFR,2nM
VEGFR2,80nM
体外研究
Sunitinib也是有效的c-Kit抑制剂，IC50?11 nM。[1] Sunitinib是有效的ATP竞争性VEGFR2 (Flk1)和PDGFR抑制剂， Ki 分别? nM 8 nM,作用于VEGFR2 PDGFR 比作用于FGFR-1, EGFR, Cdk2, Met, IGFR-1, Abl, src选择性高10多倍。Sunitinib 作用于血清饥饿处理的表达VEGFR2或PDGFR的NIH-3T3细胞, 抑制VEGF依赖 VEGFR2磷酸化和 PDGF依赖的PDGFR磷酸化，IC50分别?0 nM 10 nM。Sunitinib抑制VEGF诱导的血清饥饿处理的 HUVECs 增殖，IC50?0 nM, 且抑制PDGF诱导的过量表达PDGFR PDGFR的NIH-3T3细胞，IC50分别?9 nM 69 nM。[2] Sunitinib 抑制野生型FLT3, FLT3-ITD,和FLT3-Asp835磷酸化，IC50分别?50 nM, 50 nM, 30 nM。Sunitinib 抑制MV4;11 OC1-AML5细胞增殖，IC50分别? nM ? nM, 且诱导凋亡，这种作用存在剂量依赖性 [3]
体内研究
与体内大量且选择性抑制VEGFR2或PDGFR磷酸化和信号相一? Sunitinib每天 20-80 mg/kg 剂量处理多种移植瘤模型，包括HT-29, A431, Colo205, H-460, SF763T, C6, A375, MDA-MB-435，具有广泛且有效的抗癌活性，这种作用存在剂量依赖性。Sunitinib 每天 80 mg/kg剂量处理，持?1天，使八只鼠中有六只肿瘤完全衰退，且在处理结束后，观?10天，肿瘤不会复发。使 Sunitinib进行第二轮处理，仍然高效作用于第一轮没有完全衰退的肿瘤。Sunitinib处理SF763T胶质瘤，导致肿瘤MVD显著降低，降低～40%。SU11248 处理，完全抑制表达荧光素酶的PC-3M移植瘤生长，而肿瘤尺寸没有减小。[2] Sunitinib 每天?0 mg/kg剂量处理，显著阻断皮下MV4;11 (FLT3-ITD)移植瘤生长，且作用于FLT3-ITD骨髓移植瘤模型，抑制延长的寿命。[3]
激酶实骋/b>
Biochemical Tyrosine Kinase Assays:
IC50 values for Sunitinib against VEGFR2 (Flk-1) and PDGFR are determined using glutathione S-transferasefusion proteins containing the complete cytoplasmic domain of the RTK. Biochemical tyrosine kinase assays to quantitate the trans-phosphorylation activity of VEGFR2 (Flk-1) and PDGFR are performed in 96-well microtiter plates precoated (20 g/well in PBS; incubated overnight at 4 C) with the peptide substrate poly-Glu,Tyr (4:1). Excess protein binding sites are blocked with the addition of 1-5% (w/v) BSA in PBS. Purified GST-fusion proteins are produced in baculovirus-infected insect cells. GST-VEGFR2 and GST-PDGFR are then added to the microtiter wells in 2 concentration kinase dilution buffer consisting of 100 mM HEPES, 50 mM NaCl, 40 M NaVO4, and 0.02% (w/v) BSA. The final enzyme concentration for GST-VEGFR2 or GST-PDGFR is 50 ng/mL. Twenty-five L of diluted Sunitinib are subsequently added to each reaction well to produce a range of inhibitor concentrations appropriate for each enzyme. The kinase reaction is initiated by the addition of different concentrations of ATP in a solution of MnCl2 so that the final ATP concentrations spanned the Km for the enzyme, and the final concentration of MnCl2 is 10 mM. The plates are incubated for 5-15 minutes at room temperature before stopping the reaction with the addition of EDTA. The plates are then washed three times with TBST. Rabbit polyclonal antiphosphotyrosine antisera are added to the wells at a 1:10,000 dilution in TBST containing 0.5% (w/v) BSA, 0.025% (w/v) nonfat dry milk, and 100 M NaVO4 and incubated for 1 hour at 37 C. The plates are then washed three times with TBST, followed by the addition of goat antirabbit antisera conjugated with horseradish peroxidase (1:10,000 dilution in TBST). The plates are incubated for 1 hour at 37 C and then washed three times with TBST. The amount of phosphotyrosine in each well is quantitated after the addition of 2,2?azino-di-[3-ethylbenzthiazoline sulfonate] as substrate.
细胞实验
Cell lines: RS4;11, MV4;11, OC1-AML5
Concentrations: 溶于DMSO,终浓度为?0 M
Incubation Time: 24 ?8 小时
Method: 细胞在含0.1% FBS 的培养基上饥饿处理过夜，然后加入Sunitinib FL (50 ng/mL; FLT3-WT)。培?8小时后，使用 Alamar Blue 检测或台酚蓝细胞活力检测测定增殖。加入Sunitinib 24小时后，测量凋亡，通过Western blotting测定caspase-3水平的PARP分裂、/p>
(Only for Reference)
动物实验
Animal Models: 皮下移植 HT-29, A431, Colo205, H-460, SF763T, C6, A375, MDA-MB-435的雌性nu/nu小鼠,携带表达荧光素酶 PC-3M肿瘤的雄性nu/nu小鼠
Formulation: 配制作为羧甲基纤维素悬浮液，或作为柠檬酸缓冲?pH 3.5)
Dosages: ?0 mg/kg
Administration: 口服处理，每天一欠/p>
(Only for Reference)
参考文?/b>
[1] Sun L, et al. J Med Chem, 2003, 46(7), 1116-1119.
[2] Mendel DB, et al. Clin Cancer Res, 2003, 9(1), 327-337.
[3] O'Farrell AM, et al. Blood, 2003, 101(9), 3597-3605.
[4] Abrams TJ, et al. Mol Cancer Ther, 2003, 2(10), 1011-1021.
[5] Yee KW, et al. Blood, 2004, 104(13), 4202-4209.
[6] Ikezoe T, et al. Mol Cancer Ther, 2006, 5(10), 2522-2530.
安全信息
| 图形或危害标忖/td> |
 |
| 提示?/td> |
Danger |
| 危险说明 |
H360
H372 |
| 防范说明 |
P201
P308+P313 |
| WGK |
2 |
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