FL-411 (BRD4-IN-1)
(Synonyms: 2-(4-羟基-3,5-二甲基苯基)-7-甲基-5,6,7,8-四氢吡啶并[4',3':4,5]噻吩并[2,3-D]嘧啶-4(1H)-酮,BRD4-IN-1) 目录号 : GC33015
FL-411 (BRD4-IN-1) is a potent and selective inhibitor of Bromodomain-containing protein 4 (BRD4) with IC50 of 0.43 μM for BRD4(1). FL-411 induces ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction.
Cas No.:2118944-88-8
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: | The MCF-7 and MDA-MB-231 cells are dispensed in 96-well flat bottom microtiter plates at a density of 5×104 cells/mL. After 24 h incubation, MCF-7 or MDA-MB-231 cells are treated with 1.5 and 3 μM FL-411, respectively. 3-MA (1 mM) is added 1 h before treated with FL-411. After treatment, cell viability is measured by the MTT assay. 5 mg/mL MTT is added to each well. After 4 h incubation, the medium is removed and 150 μL of DMSO is added to each well to dissolve the crystal formazan dye. Absorbance is measured at 570 nm on an enzyme-linked immunosorbent assay reader[1]. |
Animal experiment: | Mice[1]52 female nude mice (BALB/c, 6-8 weeks, 20-22 g) are injected subcutaneously with MCF-7 cells or MDA-MB-231 cells (5×106 cells/mouse), respectively. When the tumors reach 100 mm3 in volume, the mice are divided into four groups for each cell line. Three groups are treated with different doses of FL-411 (low dose, 25 mg/kg; median dose, 50 mg/kg; high dose, 100 mg/kg) once a day by intragastric administration for 24 or 27 days, whereas the control group is treated with vehicle control. During the treatment, the tumor volumes and body weight are measured every 3 days until the end of the study. At the end of treatment, all mice are sacrificed. The tumor tissues are harvested, weighed, and photographed. Then, the tumor tissues are frozen in liquid nitrogen or fixed in formalin immediately[1]. |
References: [1]. Ouyang L, et al. Discovery of a Small-Molecule Bromodomain-Containing Protein 4 (BRD4) Inhibitor That InducesAMP-Activated Protein Kinase-Modulated Autophagy-Associated Cell Death in Breast Cancer. J Med Chem. 2017 Dec 28;60(24):9990-10012. | |
FL-411 (BRD4-IN-1) is a potent and selective inhibitor of Bromodomain-containing protein 4 (BRD4) with IC50 of 0.43 μM for BRD4(1). FL-411 induces ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction.
[1] Liang Ouyang, et al. J Med Chem. 2017 Dec 28;60(24):9990-10012.
| Cas No. | 2118944-88-8 | SDF | |
| 别名 | 2-(4-羟基-3,5-二甲基苯基)-7-甲基-5,6,7,8-四氢吡啶并[4',3':4,5]噻吩并[2,3-D]嘧啶-4(1H)-酮,BRD4-IN-1 | ||
| Canonical SMILES | CN1CCC2=C(SC(N=C(C3=CC(C)=C(O)C(C)=C3)N4)=C2C4=O)C1 | ||
| 分子式 | C18H19N3O2S | 分子量 | 341.43 |
| 溶解度 | DMSO : 5.4 mg/mL (15.82 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 | 2.9289 mL | 14.6443 mL | 29.2886 mL |
| 5 mM | 0.5858 mL | 2.9289 mL | 5.8577 mL |
| 10 mM | 0.2929 mL | 1.4644 mL | 2.9289 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 a Small-Molecule Bromodomain-Containing Protein 4 (BRD4) Inhibitor That Induces AMP-Activated Protein Kinase-Modulated Autophagy-Associated Cell Death in Breast Cancer
J Med Chem 2017 Dec 28;60(24):9990-10012.PMID:29172540DOI:10.1021/acs.jmedchem.7b00275.
Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells. Interestingly, the iTRAQ-based proteomics analyses revealed that 9f induced ACD pathways involved in HMGB1, VDAC1/2, and eEF2. Moreover, 9f displayed a therapeutic potential on both breast cancer xenograft mouse and zebrafish models. Together, these results demonstrate that a novel small-molecule inhibitor of BRD4 induces BRD4-AMPK-modulated ACD in breast cancer, which may provide a candidate drug for future cancer therapy.