BLU9931
目录号 : GC10833
A selective FGFR4 inhibitor
Cas No.:1538604-68-0
Sample solution is provided at 25 µL, 10mM.
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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.
| Kinase experiment [1]: | |
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FGFR1-4 biochemical assays |
FGFR kinase inhibition assays were performed at KM for ATP. Picomolar to low nanomolar concentrations of FGFR proteins were incubated in 1 × Kinase Reaction Buffer with 1 μM of CSKtide and 50 to 250 of μM ATP at 25 °C for 90 mins in the presence or absence of a dosed concentration series of inhibitor. All reactions were terminated by the addition of Stop Buffer, and plates were read on a Caliper EZReader2. IC50 values were fit with a four-parameter log[Inhibitor] versus response model with floating Hill Slope. |
| Cell experiment [1]: | |
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Cell lines |
MDA-MB-453, DMS114 and Hep 3B cells |
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Preparation method |
This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
0.3 ~ 300 nM; 1 hr |
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Applications |
In MDA-MB-453 cells, BLU9931 dose-dependently and effectively reduced phosphorylation of FGFR4 signaling pathway components, including FRS2, MAPK and AKT. In DMS114 cells, BLU9931 exhibited minimal reduction of phosphorylation in all FGFR1 signaling pathway components. In Hep 3B cells, BLU9931 also potently inhibited phosphorylation of the FGFR4 pathway components (except pAKT). |
| Animal experiment [1]: | |
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Animal models |
Hep 3B tumor-bearing mice |
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Dosage form |
10, 30 and 100 mg/kg; p.o.; b.i.d., for 21 days |
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Applications |
BLU9931 dose-dependently inhibited the growth of Hep 3B tumors. At the dose of 100 mg/kg, BLU9931 resulted in tumor regression. Moreover, 2 of the 9 mice showed no signs of tumor 30 days after cessation of treatment. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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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. | |
| Cas No. | 1538604-68-0 | SDF | |
| 化学名 | N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-3-methylphenyl)acrylamide | ||
| Canonical SMILES | ClC1=C(C2=CC(C=NC(NC(C(NC(C=C)=O)=CC=C3)=C3C)=N4)=C4C=C2)C(Cl)=C(OC)C=C1OC | ||
| 分子式 | C26H22Cl2N4O3 | 分子量 | 509.38 |
| 溶解度 | ≥ 50.9mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9632 mL | 9.8159 mL | 19.6317 mL |
| 5 mM | 0.3926 mL | 1.9632 mL | 3.9263 mL |
| 10 mM | 0.1963 mL | 0.9816 mL | 1.9632 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet