Sunitinib
作者：齊岳
發布時間：2023-08-23
09:15:55
點擊數：
產品名稱：Sunitinib
產品描述：
| 產品描述 | Sunitinib, a multi-targeted RTK inhibitor, is targeting PDGFRβ and VEGFR2 (Flk-1) with IC50 of 2 nM and 80 nM and also inhibits c-Kit. |
| 靶點活性 | PDGFRβ:2 nM, VEGFR2:80 nM |
| 體外活性 | 在FLT3-ITD骨髓移植模型中,Sunitinib（每天20 mg/kg）對皮下MV4;11 (FLT3-ITD)異種移植物的生長具有明顯抑制作用,并延長生存.與實質性,選擇性抑制VEGFR2或PDGFR在體內的磷酸化和信號傳導一致,Sunitinib（每天20-80 mg/kg）對各種腫瘤異種移植模型,包括HT-29,Colo205,A431,SF763T,C6,H-460,A375或MDA-MB-435表現出廣泛有效的劑量依賴性抗腫瘤活性.Sunitinib（每天80 mg/kg）給藥21天,8只小鼠中有6只的腫瘤完全消退,且在治療結束后的110天的觀察期內腫瘤沒有再生.盡管不能完全恢復到第一輪治療的情況,但在第二輪使用Sunitinib治療仍然能夠有效抗腫瘤.Sunitinib治療可使腫瘤MVD明顯下降,如在SF763T神經膠質瘤中可減少~40%.盡管腫瘤沒有減小,SU11248治療還是能夠完全抑制表達熒光素酶的PC-3M異種移植的腫瘤生長. |
| 體內活性 | Sunitinib是PDGFRβ（Ki：8 nM）和 VEGFR2 (Flk1)（Ki：9 nM）有效的ATP競爭性抑制劑。與FGFR-1,EGFR,Cdk2,Met,IGFR-1,Abl,和src相比,Sunitinib作用于VEGFR2和PDGFR的選擇性要高出10倍。在血清饑餓的表達PDGFRβ或VEGFR2的NIH-3T3細胞中,Sunitinib抑制VEGF依賴性VEGFR2磷酸化和PDGF依賴性PDGFRβ磷酸化,IC50均為10 nM。Sunitinib抑制野生型FLT3-ITD,FLT3-Asp835和FLT3磷酸化,IC50分別為50 nM,30 nM和250 nM。Sunitinib抑制OC1-AML5和MV4;11 細胞的增殖,IC50分別為14 nM和8 nM,并以劑量依賴的方式誘導細胞凋亡。Sunitinib能夠有效抑制FLT-3和Kit。對于過表達PDGFRα或PDGFRβ的NIH-3T3細胞,Sunitinib抑制VEGF對其誘導的增殖,IC50 分別為69 nM和39 nM。 |
| 激酶實驗 | Biochemical Tyrosine Kinase Assays: IC50 values for Sunitinib against VEGFR2 (Flk-1) and PDGFRβ are determined using glutathione S-transferase fusion proteins containing the complete cytoplasmic domain of the RTK. Biochemical tyrosine kinase assays to quantitate the trans-phosphorylation activity of VEGFR2 (Flk-1) and PDGFRβ are performed in 96-well microtiter plates precoated (20 μg/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-PDGFRβ are then added to the microtiter wells in 2 × concentration kinase dilution buffer consisting of 100 mM HEPES, 50 mM NaCl, 40 μM NaVO4, and 0.02% (w/v) BSA. The final enzyme concentration for GST-VEGFR2 or GST-PDGFRβ is 50 ng/mL. Twenty-five μL 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 μM 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. |
| 細胞實驗 | Cells are starved overnight in medium containing 0.1% FBS prior to addition of Sunitinib and FL (50 ng/mL; FLT3-WT cells only). Proliferation is measured after 48 hours of culture using the Alamar Blue assay or trypan blue cell viability assays. Apoptosis is measured 24 hours after Sunitinib addition by Western blotting to detect cleavage of poly (ADP-ribose) polymerase (PARP) or levels of caspase-3. (Only for Reference) |
| 別名 | SU 11248, 蘇尼替尼, 舒尼替尼 |
| 分子量 | 398.482 |
| 分子式 | C22H27FN4O2 |
| CAS No. | 557795-19-4 |
存儲
Powder: -20°C for 3 years | In solvent: -80°C for 2 years
溶解度
DMSO: 24 mg/mL (60.2 mM)
H2O: <1 mg/mL
Ethanol: <1 mg/mL
( < 1 mg/mL refers to the product slightly soluble or insoluble )
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