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Regorafenib

现货
Catalog No.
A8236
VEGFR/PDGFR/FGFR/mutant Kit/RET/Raf-1抑制剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 700.00
现货
10mg
¥ 650.00
现货
50mg
¥ 1,000.00
现货
100mg
¥ 1,600.00
现货
200mg
¥ 2,500.00
现货

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Background

Regorafenib (BAY 73-4506) is a novel and orally active multikinase inhibitor of receptor tyrosine kinases VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET, Raf-1, B-RAF and B-RAFV600E with IC50 values of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM, 2.5 nM, 28 nM and 19 nM [1].

VEGFR1/2/3 are vascular endothelial growth factor receptor plays an important role in the formation of normal and tumor vasculature. platelet-derived growth factor receptor-β (PDGFRβ) is a receptor for the platelet-derived growth factor family. Kit, RET and B-RAF are both receptor tyrosine kinases that encoded by proto-oncogenes [1].

Regorafenib (BAY 73-4506) is a novel and orally active receptor tyrosine kinases inhibitor. In NIH-3T3/VEGFR2 cells, regorafenib potently inhibited VEGFR2 autophosphorylation with IC50 value of 3 nM. Regorafenib also inhibited TIE2 and PDGFR-β autophosphorylation with IC50 values of 31 and 90 nM. Regorafenib potently inhibited KITK642E and RETC634W with IC50 values of ~20 and ~10 nM, respectively. In addition, regorafenib inhibited the proliferation of VEGF165-stimulated HUVECs with IC50 value of ~3 nM [1].

In GS9L glioblastoma xenografted rat model, regorafenib administered orally at 10 mg/kg significantly reduced the extravasation of Gadomer in the vasculature. In various preclinical human xenograft mice models, regorafenib exhibited potent dose-dependent tumor growth inhibition (TGI) [1]. In murine metastatic colorectal cancer (CRC) liver metastasis model, regorafenib significantly delayed disease progression by inhibiting the growth of liver metastases and preventing the formation of new metastases in other organs [2].

References:
[1].  Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer, 2011, 129(1): 245-255.
[2].  Schmieder R, Hoffmann J, Becker M, et al. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer, 2014, 135(6): 1487-1496.

文献引用

1. Barot S, Abo-Ali EM, et al. "Inhibition of glycogen catabolism induces intrinsic apoptosis and augments multikinase inhibitors in hepatocellular carcinoma cells." Exp Cell Res. 2019 Aug 15;381(2):288-300. PMID:31128107
2. Wu LW, Zhou DM, et al. "Suppression of LSD1 enhances the cytotoxic and apoptotic effects of regorafenib in hepatocellular carcinoma cells." Biochem Biophys Res Commun. 2019 May 14;512(4):852-858. PMID:30929918
3. Hu X, Wu LW, et al. "The anti-tumor effect of regorafenib in lung squamous cell carcinoma in vitro." Biochem Biophys Res Commun. 2018 Sep 5;503(2):1123-1129. PMID:29944884
4. Yang Q, Guo X, et al. "Metformin Enhances the Effect of Regorafenib and Inhibits Recurrence and Metastasis of Hepatic Carcinoma After Liver Resection via Regulating Expression of Hypoxia Inducible Factors 2α (HIF-2α) and 30 kDa HIV Tat-Interacting Protein (TIP30)." Med Sci Monit. 2018 Apr 14;24:2225-2234. PMID:29654226
5. Zhang WJ, Li Y, et al. "Synergistic antitumor activity of regorafenib and lapatinib in preclinical models of human colorectal cancer." Cancer Lett. 2017 Feb 1;386:100-109. PMID:27864115

Chemical Properties

Physical AppearanceA solid
StorageDesiccate at -20°C
M.Wt482.82
Cas No.755037-03-7
FormulaC21H15ClF4N4O3
SynonymsBAY 73-4506
Solubility≥25.0415mg/mL in DMSO, ≥6.25 mg/mL in EtOH with ultrasonic, <2.12 mg/mL in H2O
Chemical Name4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)-N-methylpicolinamide
SDFDownload SDF
Canonical SMILESO=C(NC)C1=CC(OC2=CC=C(NC(NC3=CC=C(Cl)C(C(F)(F)F)=C3)=O)C(F)=C2)=CC=N1
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验[1]:

细胞系

PLC/PRF/5细胞

溶解方法

在DMSO中的溶解度>10 mM。为了获得更高的浓度,可以将离心管在37℃加热10分钟和/或在超声波浴中震荡一段时间。原液可以在-20℃以下储存几个月。

反应条件

迁移实验:1 μM,72 h;侵袭实验:5 μM, 24 h

应用

在迁移实验中,PLC/PRF/5细胞用药物处理,在划痕时(T0)和48及72小时之后进行显微镜分析。在侵袭实验中,侵袭中的PLC/PRF/5细胞用不同浓度的药物处理(0.5、1、2.5和5 μM)。与对照组相比,药物处理组中侵袭细胞的百分比用于评估侵袭的发生。在AFP阳性和AFP阴性细胞中,regorafenib在抑制AFP的低浓度范围下抑制HCC细胞的迁移。在细胞侵袭实验中,regorafenib在几乎相同的药物浓度下具有相似的效果。

动物实验[2]:

动物模型

植入Colo-205、MDA-MB-231或786-O异种移植物的雌雄无胸腺NCr nu/nu小鼠

剂量

100、30、10和3 mg/kg;口服给药

应用

在多个异种移植模型中,包括CRC(Colo-205)、BC(MDA-MB-231)和RCC (786-O)肿瘤衍生的模型,regorafenib每天一次(qd)口服给药后以剂量依赖的方式抑制肿瘤生长。Regorafenib在10-100 mg/kg的剂量下有效抑制Colo-205异种移植物的生长,在10 mg/kg剂量下,在第14天时达到约75%的肿瘤生长抑制(TGI)。所有剂量组在治疗终止后的9天观察到缓慢的肿瘤再生。在MDA-MB-231模型中,regorafenib在浓度低至3 mg/kg时也具有很好的效果,导致81%的显著TGI,而在10和30 mg/kg的剂量下,TGI增加到约93%,肿瘤生长停滞。Regorafenib也可以有效抑制786-O RCC肿瘤的生长,在10和30 mg/kg剂量下给药21天后观察到大于90%的TGI。

注意事项

请测试所有化合物在室内的溶解度,实际溶解度和理论值可能略有不同。这是由实验系统的误差引起的,属于正常现象。

References:

[1] Carr B I, D'Alessandro R, Refolo M G, et al. Effects of low concentrations of regorafenib and sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro. Journal of cellular physiology, 2013, 228(6): 1344-1350.

[2] Wilhelm S M, Dumas J, Adnane L, et al. Regorafenib (BAY 73‐4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. International Journal of Cancer, 2011, 129(1): 245-255.

生物活性

描述 Regorafenib (BAY 73-4506)是一个多靶点抑制剂,作用于VEGFR1、VEGFR2、 VEGFR3、PDGFRβ、Kit、RET和Raf-1,IC50值分别为13 nM、4.2 nM、46 nM、22 nM、7 nM、1.5 nM和2.5 nM。
靶点 VEGFR1/2/3 PDGFRβ Kit RET Raf-1  
IC50 13 nM/4.2 nM/46 nM 22 nM 7 nM 1.5 nM 2.5 nM  

质量控制

化学结构

Regorafenib

相关生物数据

Regorafenib
Regorafenib inhibits growth-factor-stimulated VEGFR2 and VEGFR3 autophosphorylation in human umbilical vascular endothelialcells (HuVECs) and intracellular signaling and migration in lymphatic endothelial cells (LECs). Western blot analysis of (a) VEGFR2 and (b) VEGFR3, ERK1/2 and AKT from total cell lysates from (a) HuVECs and (b) LECs. All cells were treated with the indicated concentrations of regorafenib and subsequently stimulated with (a) VEGF-A or (b) VEGF-C. * indicates nonspeci?c signals.

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