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Nintedanib (BIBF 1120)

现货
Catalog No.
A8252
VEGFR/PDGFR/FGFR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
5mg
¥ 630.00
现货
25mg
¥ 1,620.00
现货

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Background

Nintedanib (BIBF 1120) is an indolinone-derived oral active, triple angiokinase inhibitor of vascular endothelial growth factor receptor (VEGFR)1-3, fibroblast growth factor receptor (FGFR)1-3 and platelet-derived growth factor receptor (PDGFR)α/β1. It has shown potent antiangiogenic activity at nanomolar (IC50, 20-100 nmol/L) by blocking these receptor-mediated signaling pathways1,2. Nintedanib (BIBF 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis as these receptors have been shown to be potentially involved in the pathogenesis of pulmonary fibrosis3,4. As a novel angiogenesis inhibitor, it is also being widely evaluated in different cancer models and has displayed significant anti-tumor activities by inhibiting tumor blood vessel formation5-7.

To further evaluate its antitumor effects on multiple tumors, Nintedanib is currently entering several clinical trials, including non-small cell lung cancer8, ovarian cancer6, colorectal cancer7, hepatocellular carcinoma9 and many other solid tumors. In addition, the possibilities of combining Nintedanib therapy with other treatments such as docetaxel10 and afatinib 11are being tested in different tumor models. The most common drug-related adverse events in patients were diarrhea, nausea, vomiting and lethargy7.

References:
[1]Hilberg, F. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer research 68, 4774-4782, doi:10.1158/0008-5472.CAN-07-6307 (2008).

[2]Roth, G. J. et al. Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120). Journal of medicinal chemistry 52, 4466-4480, doi:10.1021/jm900431g (2009).

[3]Wollin, L., Maillet, I., Quesniaux, V., Holweg, A. & Ryffel, B. Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis. The Journal of pharmacology and experimental therapeutics 349, 209-220, doi:10.1124/jpet.113.208223 (2014).

[4]Antoniu, S. A. Nintedanib (BIBF 1120) for IPF: a tomorrow therapy? Multidisciplinary respiratory medicine 7, 41, doi:10.1186/2049-6958-7-41 (2012).

[5]Santos, E. S., Gomez, J. E. & Raez, L. E. Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor. Investigational new drugs 30, 1261-1269, doi:10.1007/s10637-011-9644-2 (2012).

[6]Wei, X. W., Zhang, Z. R. & Wei, Y. Q. Anti-angiogenic drugs currently in Phase II clinical trials for gynecological cancer treatment. Expert opinion on investigational drugs 22, 1181-1192, doi:10.1517/13543784.2013.812071 (2013).

[7]Mross, K. et al. Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clinical cancer research : an official journal of the American Association for Cancer Research 16, 311-319, doi:10.1158/1078-0432.CCR-09-0694 (2010).

[8]Rolfo, C. et al. BIBF 1120/ nintedanib : a new triple angiokinase inhibitor-directed therapy in patients with non-small cell lung cancer. Expert opinion on investigational drugs 22, 1081-1088, doi:10.1517/13543784.2013.812630 (2013).

[9]Tai, W. T. et al. Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. Journal of hepatology, doi:10.1016/j.jhep.2014.03.017 (2014).

[10]Reck, M. et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. The lancet oncology 15, 143-155, doi:10.1016/S1470-2045(13)70586-2 (2014).

[11]Bouche, O. et al. Phase II trial of weekly alternating sequential BIBF 1120 and afatinib for advanced colorectal cancer. Anticancer research 31, 2271-2281 (2011).

文献引用

1. Mateus PAM, Kido LA, et al. "Association of anti-inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice." Prostate. 2018 Dec 25. PMID:30585351
2. Pangrazi EN, da Silva RF, et al. "Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: Contribution to the epithelial-stromal interaction balance." Cell Biol Int. 2017 Oct 5. PMID:28980742
3. Janelle DeJong."Determination of Anti-Fibrotic Effects of Possible Scar-Collagen Antagonists on TGF-β1 Treated Dermal Fibroblasts." 2017 Feb 1;7(2):203-217. eCollection 2017.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt539.62
Cas No.656247-17-5
FormulaC31H33N5O4
SynonymsVargatef
Solubility≥5.4 mg/mL in DMSO, <2.91 mg/mL in EtOH, <2.8 mg/mL in H2O
Chemical Namemethyl (3Z)-3-[[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]anilino]-phenylmethylidene]-2-oxo-1H-indole-6-carboxylate
SDFDownload SDF
Canonical SMILESCN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)NC(=C3C4=C(C=C(C=C4)C(=O)OC)NC3=O)C5=CC=CC=C5
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

PLC5、Hep3B、SK-Hep1、HuH7和HepG2细胞

制备方法

该化合物在DMSO中的溶解度大于10 mM,若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。

反应条件

20 μM,48 hours

实验结果

Nintedanib处理48小时后通过MTT实验测定细胞活力。在所有测试的HCC细胞中,Nintedanib显著诱导亚G1阳性细胞的积累。此外,通过对DNA片段化的测定也证明了nintedanib诱导凋亡。在五种HCC细胞系中,在临床相关浓度下,Nintedanib以剂量依赖性方式显著诱导DNA片段化的比例。

动物实验: [2]

动物模型

注射A459、Calu-6或H1993细胞的雌性NOD/SCID小鼠

给药剂量

口服给药,50 mg/kg,每周5天

实验结果

在A549异种移植物中,单一药剂的BIBF 1120有效地减少原发性肿瘤大小。在三种异种移植物中,所有模型中特别是在组合给药组中观察到肿瘤生长速率的降低,其中生长曲线逐渐变为线性。在所有模型中,与对照相比,BIBF 1120和组合给药组中的最终肿瘤体积和重量较低。在A549和H1993异种移植物中,组合给药比单一药剂治疗更有效;然而,在Calu-6异种移植物中,组合治疗与BIBF 1120单一药剂治疗没有明显区别。

注意事项

请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。

References:

[1] Tai W T, Shiau C W, Li Y S, et al. Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. Journal of hepatology, 2014.

[2] Cenik B K, Ostapoff K T, Gerber D E, et al. BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Molecular cancer therapeutics, 2013, 12(6): 992-1001.

生物活性

Description BIBF 1120是一种有效的三重激酶抑制剂,对VEGFR1/2/3、FGFR1/2/3 和 PDGFRα/β的IC50值分别为34 nM/13 nM/13 nM、69 nM/37 nM/108 nM和59 nM/65 nM。
靶点 VEGFR1/2/3 FGFR1/2/3 PDGFRα/β      
IC50 34 nM/13 nM/13 nM 69 nM/37 nM/108 nM 59 nM/65 nM      

质量控制

化学结构

Nintedanib(BIBF 1120)

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Nintedanib(BIBF 1120)

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Nintedanib(BIBF 1120)

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Nintedanib(BIBF 1120)

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Nintedanib(BIBF 1120)