FIIN-3
目录号 : GC36044
An inhibitor of FGFRs
Cas No.:1637735-84-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | TEL-FGFR2–transformed Ba/F3 cells are seeded in a 96-well plate and are treated with each concentration of FIIN-3. After 72 h the cells are assessed by MTS tetrazolium assay[1]. |
References: [1]. Tan L et al. Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors. Proc Natl Acad Sci U S A, 2014 Nov 11, 111(45):E4869-77 | |
FIIN-3 is an inhibitor of FGF receptors (FGFRs; IC50s = 13, 21, 31, and 35 nM for recombinant FGFR1-4, respectively).1 It is selective for FGFRs over a panel of 456 kinases at a concentration of 1 μM, however, it does inhibit EGFR (IC50 = 204 nM). FIIN-3 inhibits growth of Ba/F3 cells that are dependent on the kinase activity of wild-type FGFR1-4 as well as gatekeeper mutant FGFR2 and FGFR3 (EC50s = <1-69 nM) and inhibits FGFR-dependent signaling in a concentration-dependent manner in FGFR2TEL/V564M-dependent Ba/F3 cells. FIIN-3 also inhibits growth in a panel of cancer cell lines (EC50s = 1.4-499 nM).
1.Tan, L., Wang, J., Tanizaki, J., et al.Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitorsProc. Natl. Acad. Sci. USA111(45)E4869-E4877(2014)
| Cas No. | 1637735-84-2 | SDF | |
| Canonical SMILES | C=CC(NC1=CC=C(CN(C(NC2=C(Cl)C(OC)=CC(OC)=C2Cl)=O)C3=NC=NC(NC4=CC=C(N5CCN(C)CC5)C=C4)=C3)C=C1)=O | ||
| 分子式 | C34H36Cl2N8O4 | 分子量 | 691.61 |
| 溶解度 | DMSO: 10 mg/mL (14.46 mM and warming); Water: < 0.1 mg/mL (insoluble) | 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 | 1.4459 mL | 7.2295 mL | 14.459 mL |
| 5 mM | 0.2892 mL | 1.4459 mL | 2.8918 mL |
| 10 mM | 0.1446 mL | 0.723 mL | 1.4459 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。
Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors
Proc Natl Acad Sci U S A 2014 Nov 11;111(45):E4869-77.PMID:25349422DOI:PMC4234547
The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.