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Sunitinib (Malate) | 苹果酸舒尼替尼

MCE 国际站：Sunitinib (Malate)

中文名：苹果酸舒尼替尼

CAS：341031-54-7

品牌：MedChemExpress (MCE)

存储条件：Please store the product under the recommended conditions in the Certificate of Analysis.

生物活性：Sunitinib Malate (SU 11248 Malate) 是一种多靶点受体酪氨酸激酶抑制剂，抑制 VEGFR2 和 PDGFRβ 的 IC50 分别为80 nM 和 2 nM。Sunitinib Malate 是ATP 竞争性抑制剂，可通过抑制自身磷酸化和随后的 RNase 激活来有效抑制 Ire1α 的磷酸化。

体外：Sunitinib Malate is also a good inhibitor of KIT ａnd FLT-3[1]. In RS4;11 cells (FLT3-WT), treatment with Sunitinib (SU11248) inhibits FLT3-WT phosphorylation in a dose-dependent manner with IC50 of approximately 250 nM. In MV4;11 cells that express FLT3-ITD, Sunitinib inhibits FLT3-ITD phosphorylation in a dose-dependent manner with an IC50 of 50 nM following a 2-hour treatment[3].In biochemical assays, Sunitinib (SU11248) exhibits competitive inhibition (with regard to ATP) against Flk-1 ａnd PDGFRβ with Ki values of 9 nM ａnd 8 nM, respectively. Sunitinib is also a competitive, albeit less potent, inhibitor of FGFR1 tyrosine kinase activity, with a Ki value of 0.83 μM. In addition to these three structurally related split kinase domain RTKs, the activity of Sunitinib has also been evaluated against a broad panel of additional tyrosine ａnd serine/threonine kinases. In these biochemical assays, the IC50 values for Sunitinib are generally at least 10-fold higher than those for Flk-1 ａnd PDGFR (e.g., IC50values of: >10 μM for EGFR ａnd Cdk2; 4 μM for Met; 2.4 μM for IGFR-1; 0.8 μM for Abl; ａnd 0.6 μM for Src)[4]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

体内：Sunitinib Malate has very good oral bioavailability, is highly efficacious in a number of preclinical tumor models, ａnd is well tolerated at efficacious doses[1]. Sunitinib (80 mg/kg/day) inhibits the growth of established SF763T ａnd Colo205 tumor xenografts in athymic mice. Sunitinib (SU11248) treatment effectively inhibits the growth of established tumor xenografts[4]. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Clinical Trial

激酶试验：进行生化测定以确定舒尼替尼针对不同蛋白激酶的活性。 SU11248 针对 Flk-1、PDGFRβ 和 FGFR1 的 Ki 值是使用包含 RTK 完整胞质结构域的谷胱甘肽 S-转移酶融合蛋白测定的。使用经 40 ng/mL VEGF165 (Flk-1/KDR)、0.5 μg/mL 碱性 FGF 刺激的血清饥饿细胞进行细胞测定，直接测定 SU11248 抑制配体依赖性 RTK 磷酸化或细胞增殖和有丝分裂反应的能力(FGFR) 或 50 ng/mL PDGF-AA (PDGFRα) 或 PDGF-BB (PDGFRβ)[2]。

细胞试验：将 RS4;11 和 MV4;11 细胞系在含有 0.1% FBS 的培养基中饥饿过夜，然后添加 SU11248（1 nM、5 nM、10 nM、25 nM、75 nM、100 nM、250 nM、500 nM）和 FL （50 ng/mL；仅限 FLT3-WT 细胞）。培养 48 小时后，按照制造商的说明，使用 Alamar Blue 测定法对每种条件进行三次重复测量增殖。台盼蓝细胞活力测定是平行进行的并产生相似的结果[3]。

动物体内实验:小鼠[2] 使用雌性nu/nu小鼠（8-12周龄，25克）。简而言之，在第 0 天将 3-5×106 个肿瘤细胞皮下植入小鼠的后胁区。每天口服 SU11248 治疗荷瘤小鼠，以羧甲基纤维素悬浮液或柠檬酸盐缓冲（pH 3.5）溶液的形式进行治疗一旦肿瘤达到指定的平均大小就开始。根据每周两次测量肿瘤体积来评估肿瘤生长。通常，当经载体处理的动物的肿瘤平均大小达到 1000 mm3 或当判断肿瘤对动物的健康产生不利影响时，研究就会终止。大鼠[4]使用四十只雌性Sprague-Dawley大鼠(200-230g)。每组由5-10只自由采食的动物组成。在气体麻醉（2%异氟烷）下将1×104 Walker 256细胞注射到左腹部乳腺脂肪垫中。每天对大鼠称重，并通过强饲法给予苹果酸舒尼替尼（30 mg/kg）和/或芬戈莫德（5 mg/kg）橄榄油溶液。用卡尺测量肿瘤。在肿瘤溃疡之前，通过心内注射氯胺酮（50 mg/mL）麻醉并杀死动物。解剖大鼠以检测肺、肝、肾或肠转移。

研究领域：Protein Tyrosine Kinase/RTK | Cell Cycle/DNA Damage | Autophagy | Apoptosis

参考文献：

[1]. Sun L, et al. Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial ａnd platelet-derived growth factor r[2]. Ali MM, et al. Structure of the Ire1 autophosphorylation complex ａnd implications for the unfolded protein response. EMBO J. 2011 Mar 2;30(5):894-905.[3]. O＇Farrell AM, et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro ａnd in vivo. Blood. 2003 May 1;101(9):3597-605.[4]. Mendel DB, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor ａnd platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Can