呋喹替尼作用機制 - Medchemexpress - MCE中國

1、Product Data SheetFruquintinibCat. No.: HY-19912CAS No.: 1194506-26-7分式: CHNO分量: 393.39作靶點: VEGFR作通路: Protein Tyrosine Kinase/RTK儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數據體外實驗 DMSO : 5.88 mg/mL (14.95 mM; Need ultrasonic)SolventMass1 mg 5 mg 10 mgConcentration制備儲備液1

2、mM 2.5420 mL 12.7100 mL 25.4201 mL5 mM 0.5084 mL 2.5420 mL 5.0840 mL10 mM 0.2542 mL 1.2710 mL 2.5420 mL請根據產品在不同溶劑中的溶解度選擇合適的溶劑配制儲備液；旦配成溶液，請分裝保存，避免反復凍融造成的產品失效。儲備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲存時，請在 6 個內使，-20C 儲存時，請在 1 個內使。體內實驗請根據您的實驗動物和給藥式選擇適當的溶解案。以下溶解案都請先按照 In Vitro 式配制澄清的儲備液，再依次添加助溶劑：為

3、保證實驗結果的可靠性，澄 的儲備液可以根據儲存條件，適當保存；體內實驗的作液，建議您現現配，當天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現沉淀、析出現象，可以通過加熱和/或超聲的式助溶1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 0.59 mg/mL (1.50 mM); Clear solution此案可獲得 0.59 mg/mL (1.50 mM，飽和度未知) 的澄清溶液。以 1 mL 作液為例，取 100 L 5.8999996 mg/mL 的澄清DMSO 儲備液

4、加到 400 L PEG300 中，混合均勻；向上述體系中加 50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 0.59 mg/mL (1.50 mM); Clear solution此案可獲得 0.59 mg/mL (1.50 mM，飽和度未知) 的澄清溶液。Page 1 of 2 www.MedChemE以 1 mL 作液為例，取 100 L 5.8999996 mg/mL 的澄，混合均勻。DMSO 儲備液加到 900 L 20% 的 S

5、BE-CD 理鹽溶液中3. 請依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 0.59 mg/mL (1.50 mM); Clear solution此案可獲得 0.59 mg/mL (1.50 mM，飽和度未知) 的澄 溶液，此案不適于實驗周 期在半個以上的實驗。以 1 mL 作液為例，取 100 L 5.8999996 mg/mL 的澄 DMSO 儲備液加到 900 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 Fruquintinib (HMPL-013)是有效，選擇性的 VEGFR 1/2/3 抑制劑，IC50 值分別為33，0

6、.5，and 35 nM。IC & Target VEGFR1 VEGFR2 VEGFR333 nM (IC50) 35 nM (IC50) 0.5 nM (IC50)體外研究 Fruquintinib demonstrates potent inhibition on VEGF-A dependent KDR phosphorylation in HEK293-KDR cells andVEGF-A induced proliferation in primary HUVECs with IC50s of 0.60.2 nM and 1.7 nM, respectively. Similar

7、ly, potentVEGFR3 attenuation by fruquintinib is observed in primary HLECs, with IC50s of 1.5 nM and 4.2 nM for VEGF-Cstimulated VEGFR3 phosphorylation and proliferation, respectively. Fruquintinib suppresses the tube branching, tubelength and area in a concentration-dependent manner. The tubule leng

8、th of primary HUVECs decreased by 74% and94% at 0.03 and 0.3 M of fruquintinib, respectively. Fruquintinib inhibits HUVEC tubule growth and CAMangiogenesis. Tube formation is suppressed significantly after treatment with fruquintinib at 0.3 M for 18 hours1.體內研究 Gastric cancer BGC-823 model is found

9、to be most sensitive to fruquintinib. In this model, fruquintinib inhibits tumorgrowth by 62.3% and 95.4-98.6%, at 0.5 and 2 mg/kg once daily dosing, respectively. When the dose is elevated to 5 mg/kg and 20 mg/kg, the tumors regress by 24.1% and 48.6%, respectively. The level of anti-tumor growth a

10、ctivity offruquintinib varies in different tumor xenograft models. Fruquintinib significantly decreases the micro-vessel densityeven at the lowest dose of 0.8 mg/kg1.PROTOCOLCell Assay 1 Primary HUVECs or HLECs in exponential phase are suspended in 100 L of RPMI-1640 media containing 0.5% FBS,and se

11、eded at 5000 cell/well in 96-well plates pre-coated with 0.2% gelatin or fibronectin, and incubated overnight ina 5% CO2, 37C incubator. Fruquintinib and VEGF-A165 or VEGF-C (50 ng/mL) are added and incubated for 48 hours.Viability of the cells is determined using CCK-8 assay format1.MCE has not ind

12、ependently confirmed the accuracy of these methods. They are for reference only.Animal Mice: The patient derived xenograft models are established after the primary tumor adopted serial passages in vivo.Administration 1 Once tumors have grown to 100-300 mm3, the animals are randomly assigned with 6-8

13、 animals per group. The miceare treated orally with the vehicle (control group) or fruquintinib at a dose range of 0.5-20 mg/kg suspended in thevehicle (treated group) once daily for 3 weeks. In combination studies, docetaxel (Taxotere, 5 mg/kg) or oxaliplatin(10 mg/kg) is administered to nude mouse

14、 via intravenous injection, once a week. Tumor size and body weights aremeasured 3 times a week. Tumor volumes (TV) are calculated1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCESPage 2 of 3 www.MedChemE1. Sun Q, et al. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. CancerBiol Ther. 2014;15(12):1635-45.MceP