切换导航

BLU9931

现货
Catalog No.
A8706
有效的FGFR4不可逆抑制剂
组合的产品项目
规格价格库存 数量
5mg
¥ 1,100.00
现货
25mg
¥ 3,300.00
现货

电话: 021-55669583

邮箱: sales@apexbio.cn

全球经销商

Background

BLU9931 is a potent and irreversible inhibitor of FGFR4. BLU9931 potently inhibited FGFR4 activity (IC50 = 3 nmol/L), but weakly inhibited FGFR1 (IC50 = 591 nmol/L), FGFR2 (IC50 = 493 nmol/L), and FGFR3 (IC50 = 150 nmol/L) activity.
Fibroblast growth factor receptor 4 (FGFR4) is the receptor of fibroblast growth factor 19 (FGF19), which is a tightly controlled hormone that regulates bile acid synthesis and hepatocyte proliferation in the normal liver. FGFR4 acts as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is highly selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 binds within the ATP-binding pocket of FGFR4, forming a covalent bond with Cys552. The anilino-quinazoline core of BLU9931 makes a bidentate hydrogen-bonding interaction with the hinge residue (Ala553) of FGFR4, whereas the dichlorodimethoxyphenyl group occupies the hydrophobic pocket, providing FGFR-family selectivity. BLU9931 displayed significant binding to only two of the 398 wild-type kinases, FGFR4 (99.7% inhibition relative to DMSO control; Kd = 6 nmol/L) and CSF1R (90.1% inhibition relative to DMSO control; Kd = 2716 nmol/L) by KINOMEscan method. [2]
BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification.
References:
[1]. Hagel M, Miduturu C, Sheets M et al.First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015 Mar 16. [Epub ahead of print]
[2]. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.

Chemical Properties

StorageStore at -20°C
M.Wt509.38
Cas No.1538604-68-0
FormulaC26H22Cl2N4O3
Solubility≥50.9mg/mL in DMSO
Chemical NameN-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-3-methylphenyl)acrylamide
SDFDownload SDF
Canonical SMILESClC1=C(C2=CC(C=NC(NC(C(NC(C=C)=O)=CC=C3)=C3C)=N4)=C4C=C2)C(Cl)=C(OC)C=C1OC
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

激酶实验 [1]:

FGFR1-4生化实验

FGFR激酶抑制试验在针对ATP的KM值下进行。加入或不加入一系列浓度的抑制剂,将皮摩尔至纳摩尔浓度的FGFR蛋白加入含1 μM CSKtide和50 ~ 250 μM ATP的1 × 激酶反应缓冲液中,将其置于25 °C下培育90分钟。加入终止缓冲液停止所有反应。在Caliper EZReader2上读取数据。使用四参数log[抑制剂]对效应模型拟合求IC50值,曲线中点不固定。

细胞实验 [1]:

细胞系

MDA-MB-453、DMS114和Hep 3B细胞

制备方法

该化合物可溶于DMSO。若配制更高浓度的溶液,一般步骤如下:请将试管置于37 °C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 °C可放置数月。

反应条件

0.3 ~ 300 nM;1小时

实验结果

在MDA-MB-453细胞中,BLU9931呈剂量依赖性地有效减少FGFR4信号传导途径组分(包括FRS2、MAPK和AKT)的磷酸化。在DMS114细胞中,BLU9931对FGFR1信号传导途径组分磷酸化的抑制作用最弱。在Hep 3B细胞中,BLU9931也能有效抑制FGFR4途径组分(除了pAKT)的磷酸化。

动物实验 [1]:

动物模型

携带Hep 3B肿瘤的小鼠

给药剂量

10、30和100 mg/kg;口服给药;每日2次,持续21日

实验结果

BLU9931呈剂量依赖性地抑制Hep 3B肿瘤生长。在100 mg/kg剂量下,BLU9931导致肿瘤消退。 此外,在9只小鼠中,2只于停止治疗后30天没有显示肿瘤复发。

其它注意事项

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]. Hagel M, Miduturu C, Sheets M, Rubin N, Weng W, Stransky N, Bifulco N, Kim JL, Hodous B, Brooijmans N, Shutes A, Winter C, Lengauer C, Kohl NE, Guzi T. First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway. Cancer Discov. 2015 Apr;5(4):424-37.

质量控制

化学结构

BLU9931