Roblitinib
(Synonyms: 8-二氮杂萘-1(2H)-甲酰胺,FGF-401) 目录号 : GC19154
Roblitinib (FGF-401) 是一种 1,8-naphthyridine 吡啶衍生物。
Cas No.:1708971-55-4
Sample solution is provided at 25 µL, 10mM.
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Roblitinib (FGF-401) is a 1,8-naphthyridine pyridine derivative[5].Roblitinib binds to an inactive (autoinhibited brake, closed activation segment) DFG-Din enzyme form; the ligand binds covalently to FGFR4 and is classified as a Type VI inhibitor[7].
Roblitinib as an orally active and highly selective FGFR4 inhibitor with an IC50 of 1.9 nM without off-target effects[3]. Roblitinib has antitumor activity[4]
In mice, PKM2-IN-1 treatment markedly decreased the tumor volume and tumor weight, compared with the control group. Meanwhile, no significant weight reduction was detected in the mouse treated with PKM2-IN-1, suggesting that PKM2-IN-1 did not cause any major organ toxicity. Thus, use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer[6].In hearts of 7-day-old mice, PKM2-specific inhibitor PKM2-IN-1 significantly blocked the proliferation of cardiomyocytes in HRR groups, indicating HRR-induced proliferation of cardiomyocytes was fully abolished by PKM2-IN-1[2]
References:
[1]: Zou Y, Zheng S, et,al. N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun. 2022 May 13;13(1):2672. doi: 10.1038/s41467-022-30217-7. PMID: 35562334; PMCID: PMC9106694.
[2]: Chan SL, Schuler M, et,al. A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors. J Exp Clin Cancer Res. 2022 Jun 2;41(1):189. doi: 10.1186/s13046-022-02383-5. PMID: 35655320; PMCID: PMC9161616.
[3]: National Center for Biotechnology Information (2022). PubChem Patent Summary for US-9266883-B2. Retrieved September 6, 2022 from https://pubchem.ncbi.nlm.nih.gov/patent/US-9266883-B2.
[4]: Fairhurst RA, Knoepfel T, et,al. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4. J Med Chem. 2020 Nov 12;63(21):12542-12573. doi: 10.1021/acs.jmedchem.0c01019. Epub 2020 Oct 1. PMID: 32930584.
[5]: Roskoski R Jr. The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder. Pharmacol Res. 2020 Jan;151:104567. doi: 10.1016/j.phrs.2019.104567. Epub 2019 Nov 23. PMID: 31770593.
[6]: Zhou Z , Chen X , et,al. Characterization of FGF401 as a reversible covalent inhibitor of fibroblast growth factor receptor 4. Chem Commun (Camb). 2019 May 21;55(42):5890-5893. doi: 10.1039/c9cc02052g. PMID: 31041948.
[7]: Roskoski R Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res. 2016 Jan;103:26-48. doi: 10.1016/j.phrs.2015.10.021. Epub 2015 Oct 31. PMID: 26529477.
[8]: Weiss A, Adler F, et,al. FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer. Mol Cancer Ther. 2019 Dec;18(12):2194-2206. doi: 10.1158/1535-7163.MCT-18-1291. Epub 2019 Aug 13. PMID: 31409633.
Roblitinib (FGF-401) 是一种 1,8-naphthyridine 吡啶衍生物[5]。Roblitinib 与非活性（自动抑制制动，闭合激活片段）DFG-Din 酶形式结合；配体与 FGFR4 共价结合，被归类为 VI 型抑制剂[7]。
Roblitinib 作为一种具有口服活性和高选择性 FGFR4 抑制剂，IC50 为 1.9 nM，无脱靶效应[3]。 Roblitinib 具有抗肿瘤活性[4]
在小鼠中，与对照组相比，PKM2-IN-1 治疗显着降低了肿瘤体积和肿瘤重量。同时，在用 PKM2-IN-1 处理的小鼠中未检测到明显的体重减轻，表明 PKM2-IN-1 不会引起任何主要器官毒性。因此，使用特定的 PKM2 抑制剂来阻断糖酵解途径和靶向癌细胞代谢是治疗 PKM2 过表达卵巢癌的一种很有前途的治疗方法[6]。在 7 日龄小鼠的心脏中， PKM2 特异性抑制剂 PKM2-IN-1 显着阻断 HRR 组心肌细胞的增殖，表明 PKM2-IN-1 完全消除了 HRR 诱导的心肌细胞增殖[2]
| Cell experiment [1]: | |
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Cell lines |
Hep3B, JHH7, and HUH7 cells |
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Preparation Method |
Roblitinib was dissolved at 10 mmol/L in 100% DMSO to use |
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Reaction Conditions |
Roblitinib 5nM,500nM for 1h-72h |
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Applications |
Roblitinib inhibited FGFR4 tyrosine phosphorylation at compound concentrations needed to inhibit cell proliferation. |
| Animal experiment [2]: | |
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Animal models |
Four-week-old female BALB/c nude mice |
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Preparation Method |
Cells mixed with 1:1 Matrigel were subcutaneously injected into the fat pads of mice. The mice were randomized into four groups, and they were treated with vehicle, trastuzumab, Roblitinib (30 mg/kg, oral administration). The tumor volume was measured every 3 days. |
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Dosage form |
Roblitinib (30 mg/kg, oral administration) |
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Applications |
Compared with the other treatment group, the roblitinib treatment group showed decreased tumor volume. The combination of roblitinib and other drugs revealed a synergistic antitumor effect in trastuzumab-resistant breast cancer. |
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References: [1]. Weiss A, Adler F, et,al. FGF401, A First-In-Class Highly Selective and Potent FGFR4 Inhibitor for the Treatment of FGF19-Driven Hepatocellular Cancer. Mol Cancer Ther. 2019 Dec;18(12):2194-2206. doi: 10.1158/1535-7163.MCT-18-1291. Epub 2019 Aug 13. PMID: 31409633. [2]. Zou Y, Zheng S, et,al. N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nat Commun. 2022 May 13;13(1):2672. doi: 10.1038/s41467-022-30217-7. PMID: 35562334; PMCID: PMC9106694. |
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| Cas No. | 1708971-55-4 | SDF | |
| 别名 | 8-二氮杂萘-1(2H)-甲酰胺,FGF-401 | ||
| Canonical SMILES | CN1CC(N(CC2=CC(CCCN3C(NC4=CC(NCCOC)=C(C#N)C=N4)=O)=C3N=C2C=O)CC1)=O | ||
| 分子式 | C25H30N8O4 | 分子量 | 506.56 |
| 溶解度 | DMSO : 6 mg/mL (11.84 mM) | 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 | 1.9741 mL | 9.8705 mL | 19.741 mL |
| 5 mM | 0.3948 mL | 1.9741 mL | 3.9482 mL |
| 10 mM | 0.1974 mL | 0.987 mL | 1.9741 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: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet