FN-1501
目录号 : GC33049
FN-1501 is a potent inhibitor of Fms-like receptor tyrosine kinase 3 (FLT3) and cyclin-dependent kinase (CDK), with IC50s of 2.47, 0.85, 1.96, and 0.28 nM for CDK2/cyclin A, CDK4/cyclin D1, CDK6/cyclin D1 and FLT3, respectively.
Cas No.:1429515-59-2
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
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Kinase experiment: |
The activity of the CDKs and FLT3 are assayed in reaction buffer (20 mM HEPES pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO) at room temperature at a final ATP concentration of 10 mM. Then FLT3, dissolved in 100% DMSO at the indicated doses, are delivered into the kinase reaction mixture by acoustic technology and incubated for 20 min at room temperature. After 10 μM [γ-33P] ATP (specific activity 10 Ci/μL) is added to initiate the reaction, the reactions are carried out at 25°C for 120 min. The kinase activities are detected by the filterbinding method. IC50 values and curve fits are obtained by Prism[1]. |
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Cell experiment: |
The human AML cell line MV4-11 is cultured in IMDM media with 10% FBS and supplemented with 2% l-glutamine and 1% penicillin/streptomycin. The MV4-11 cell line is maintained in culture media at 37°C with 5% CO2. The effects of FN-1501 on MV4-11 proliferation are performed. Cells are cultured in 96-well culture plates (10 000 cells/well). FN-1501 at various concentrations is added to the plates. Cell proliferation is determined after treatment with FN-1501 for 72 h. Cell viability is measured using the CellTiter-Glo assay, and luminescence is measured in a multilabel reader. Data are normalized to control groups (DMSO) and represented as the means of three independent measurements with standard errors of |
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Animal experiment: |
Mice[1]Six-week-old female nu/nu mice are housed in a specific pathogen-free facility. Prior to implantation, cells are harvested during exponential growth. Five million MV4-11 cells in PBS are formulated as a 1:1 mixture with a Matrigel and injected into the subcutaneous space on the right flank of each nu/nu mouse. Daily intravenous injections are initiated when MV4-11 tumors have reached sizes of 100-200 mm3. The animals are then randomized into treatment groups of 8 mice each for the efficacy studies and dosed with FN-1501 (0, 15, 30, or 40 (mg/kg)/d) or cytarabine (50 (mg/kg)/d). The compounds (FN-1501, etc.) are dissolved in a solution of PEG400 (25%), ethanol (3.7%), glucose (5%), and acetic acid/sodium acetate buffer (pH 4.5, 7.5%). Tumor growth is measured every 3 days using Vernier calipers for the duration of the treatment. The volume is calculated as follows: tumor volume = a × b2/2, where a is the long diameter, and b is the short diameter. The percentage of tumor-growth inhibition (GI) is calculated as follows: GI = 100% × {1 - [(tumor volumefinal - tumor volumeinitial for the compound-treated group)/(tumor volumefinal - tumor volumeinitial for the vehicle-treated group)]}. The percent tumor regression (PTR) is calculated as follows: PTR = 100% × (tumor volumeinitial - tumor volumefinal)/(tumor volumeinitial)[1]. |
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References: [1]. Wang Y, et al. Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. J Med Chem. 2018 Feb 22;61(4):1499-1518. |
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FN-1501 is a potent inhibitor of Fms-like receptor tyrosine kinase 3 (FLT3) and cyclin-dependent kinase (CDK), with IC50s of 2.47, 0.85, 1.96, and 0.28 nM for CDK2/cyclin A, CDK4/cyclin D1, CDK6/cyclin D1 and FLT3, respectively.
[1] Wang Y, et al. J Med Chem. 2018 Feb 22;61(4):1499-1518.
| Cas No. | 1429515-59-2 | SDF | |
| Canonical SMILES | O=C(C1=NNC=C1NC2=NC=NC3=C2C=CN3)NC4=CC=C(CN5CCN(C)CC5)C=C4 | ||
| 分子式 | C22H25N9O | 分子量 | 431.49 |
| 溶解度 | DMSO : ≥ 50 mg/mL (115.88 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 | 2.3176 mL | 11.5878 mL | 23.1755 mL |
| 5 mM | 0.4635 mL | 2.3176 mL | 4.6351 mL |
| 10 mM | 0.2318 mL | 1.1588 mL | 2.3176 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。
Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia
J Med Chem 2018 Feb 22;61(4):1499-1518.PMID:29357250DOI:10.1021/acs.jmedchem.7b01261.
A series of 1-H-pyrazole-3-carboxamide derivatives have been designed and synthesized that exhibit excellent FLT3 and CDK inhibition and antiproliferative activities. A structure-activity-relationship study illustrates that the incorporation of a pyrimidine-fused heterocycle at position 4 of the pyrazole is critical for FLT3 and CDK inhibition. Compound 50 (FN-1501), which possesses potent inhibitory activities against FLT3, CDK2, CDK4, and CDK6 with IC50 values in the nanomolar range, shows antiproliferative activities against MV4-11 cells (IC50: 0.008 μM), which correlates with the suppression of retinoblastoma phosphorylation, FLT3, ERK, AKT, and STAT5 and the onset of apoptosis. Acute-toxicity studies in mice show that compound 50 (LD50: 186 mg/kg) is safer than AT7519 (32 mg/kg). In MV4-11 xenografts in a nude-mouse model, compound 50 can induce tumor regression at the dose of 15 mg/kg, which is more efficient than cytarabine (50 mg/kg). Taken together, these results demonstrate the potential of this unique compound for further development into a drug applied in acute-myeloid-leukemia (AML) therapeutics.
Design and Synthesis of 4-(Heterocyclic Substituted Amino)-1 H-Pyrazole-3-Carboxamide Derivatives and Their Potent Activity against Acute Myeloid Leukemia (AML)
Int J Mol Sci 2019 Nov 15;20(22):5739.PMID:31731727DOI:10.3390/ijms20225739.
Fms-like receptor tyrosine kinase 3 (FLT3) has been emerging as an attractive target for the treatment of acute myeloid leukemia (AML). By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1H-pyrazole-3-carboxamide derivatives were designed and synthesized. Compound 8t showed strong activity against FLT3 (IC50: 0.089 nM) and CDK2/4 (IC50: 0.719/0.770 nM), which is more efficient than FN-1501(FLT3, IC50: 2.33 nM; CDK2/4, IC50: 1.02/0.39 nM). Compound 8t also showed excellent inhibitory activity against a variety of FLT3 mutants (IC50 < 5 nM), and potent anti-proliferative effect within the nanomolar range on acute myeloid leukemia (MV4-11, IC50: 1.22 nM). In addition, compound 8t significantly inhibited the proliferation of most human cell lines of NCI60 (GI50 < 1 μM for most cell lines). Taken together, these results demonstrated the potential of 8t as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics.
CRMP2 is a therapeutic target that suppresses the aggressiveness of breast cancer cells by stabilizing RECK
Oncogene 2020 Sep;39(37):6024-6040.PMID:32778769DOI:10.1038/s41388-020-01412-x.
Metastatic breast cancer is characterized by high mortality and limited therapeutic target. During tumor metastasis, cytoskeletal reorganization is one of the key steps in the migration and invasion of breast cancer cells. Collapsin response mediator protein 2 (CRMP2) is a cytosolic phosphoprotein that plays an important role in regulating cytoskeletal dynamics. Previous researches have reported that altered CRMP2 expression is associated with breast cancer progression, but the underlying mechanism remains poorly understood. Here, we show that CRMP2 expression is reduced in various subtypes of breast cancers and negatively correlated with lymphatic metastasis. Overexpression of CRMP2 significantly inhibits invasion and stemness in breast cancer cells, while downregulation of CRMP2 promotes cell invasion, which is not required for tubulin polymerization. Mechanistic studies demonstrate that CRMP2 interacts with RECK, prevents RECK degradation, which, in turn, blocks NF-κB and Wnt signaling pathways. Furthermore, we find that phosphorylation of CRMP2 at T514 and S522 remarkably abolishes its functions to bind with RECK and to inhibit cell invasion. Pharmacologic rescue of CRMP2 expression suppressed breast cancer metastasis in vitro and in vivo and stimulated a synergetic effect with FN-1501 that induces CRMP2 dephosphorylation. Collectively, this study highlights the potential of CRMP2 as a therapeutic target in breast cancer metastasis and reveals a distinct mechanism of CRMP2.