R428
(Synonyms: R-428;R 428;BGB324) 目录号 : GC17618
R428作为一种Axl抑制剂,在纳摩尔浓度下阻断Axl在其C端对接位点Tyr821上的自动磷酸化。
Cas No.:1037624-75-1
Sample solution is provided at 25 µL, 10mM.
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- Purity: >99.50%
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| Cell experiment [1]: | |
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Cell lines |
B-CPAP cell line(derived from human PTC cancer tissue) |
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Preparation Method |
The B-CPAP cell line was cultured and treated with the AXL inhibitor R428 at different concentrations (0.5 µmol/L, 1 µmol/L, 2 µmol/L, 4 µmol/L), and the untreated B-CPAP cell line was used as a control group. A CCK-8 assay was performed to assess the cell proliferation rate. |
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Reaction Conditions |
0.5 µmol/L, 1 µmol/L, 2 µmol/L, 4 µmol/L; for 24 h |
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Applications |
In the B-CPAP experimental group, the cell survival rates after treatment with 0.5, 1.0, 2.0, and 4.0 µmol/L R428 were 85.28% ± 9.21%, 66.74% ± 3.88%, 41.51% ± 6.33%, and 3.71% ± 2.10%, respectively. |
| Animal experiment [2]: | |
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Animal models |
NOD-SCID male mice |
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Preparation Method |
In the animal model, ESCC (Esophageal squamous cell carcinoma) xenograft models were established by injecting KYSE-70 cells with Matrigel into the upper back region of NOD-SCID male mice followed by treatment with vehicle control, R428 (50 mg/kg/day), cisplatin (1.0 mg/kg), or cabozantinib (30 mg/kg/day) for the indicated number of days. |
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Dosage form |
50 mg/kg/day; i.p. |
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Applications |
R428 alone significantly inhibited ESCC tumor growth compared to the vehicle; however, no synergistic effect with cisplatin was observed. |
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References: [1] Wei M, et al. AXL, along with PROS1, is overexpressed in papillary thyroid carcinoma and regulates its biological behaviour. World J Surg Oncol. 2022 Oct 6;20(1):334. |
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R428, as a Axl inhibitor, blocks Axl autophosphorylation on its C-terminal docking site, Tyr821, at nanomolar concentrations[1].
In vitro, R428 inhibited growth of H1299, a human non-small cell lung carcinoma cell line that had constitutively activated Axl, in a dose-dependent manner with an IC50 of approximately 4 µM[1]. In CE81T cells, the IC50 value of R428 was 1.98 µM when treated for 72 h[2]. In vitro, TNBC cells were treated with 0.5, 1 or 2 µM R428 for 30 min, 1-, 2- and 4-h disrupted the polarized localization of the Golgi apparatus towards the leading edge in migratory cells[3].
In vivo, rats were administrated 100 mg/kg body weight (p.o.) R428 that shown more severe RV hypertrophy, augmented right ventricular systolic pressure (RVSP), impaired cardiac output and worsened tricuspid annular plane systolic excursion, and a significantly increased total pulmonary vascular resistance index[4]. In vivo efficacy test it shown that R428 has a long plasma half-life (13 hours at 75 mg/kg), and distributes effectively to tissue[5].
In vivo, mice (8 weeks of age) were treated with 125 mg/kg R428 orally significantly reduced number of CD4+ T cells in the kidney compared to the T cell numbers in the kidney of nephritic B6 mice[6].
References:
[1] Chen F, et al. Axl inhibitor R428 induces apoptosis of cancer cells by blocking lysosomal acidification and recycling independent of Axl inhibition. Am J Cancer Res. 2018 Aug 1;8(8):1466-1482.
[2] Yang PW, et al. Cabozantinib (XL184) and R428 (BGB324) Inhibit the Growth of Esophageal Squamous Cell Carcinoma (ESCC). Front Oncol. 2019 Nov 6;9:1138.
[3] Zajac O, et al. AXL Controls Directed Migration of Mesenchymal Triple-Negative Breast Cancer Cells. Cells. 2020 Jan 19;9(1):247.
[4] Novoyatleva T, et al. Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2. Commun Biol. 2021 Aug 24;4(1):1002. doi: 10.1038/s42003-021-02531-1. Erratum in: Commun Biol. 2022 Jan 20;5(1):97.
[5] Zhen Y, et al. Targeted inhibition of Axl receptor tyrosine kinase ameliorates anti-GBM-induced lupus-like nephritis. J Autoimmun. 2018 Sep;93:37-44.
[6] Zhen Y, et al. Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis. Arthritis Res Ther. 2022 Dec 28;24(1):284.
R428作为一种Axl抑制剂,在纳摩尔浓度下阻断Axl在其C端对接位点Tyr821上的自动磷酸化[1]。
在体外,R428以剂量依赖的方式抑制H1299的生长,H1299是一种人类非小细胞肺癌细胞系,它具有构成性激活的Axl,IC50约为4µM[1]。在CE81T细胞中,处理72小时时,R428的IC50值为1.98 µM[2]。在体外,用0.5、1或2 µM的R428处理TNBC细胞30分钟,1、2和4小时,破坏了迁移细胞中高尔基体向前缘的极化定位[3]。
在体内,大鼠服用100 mg/kg (p.o.)的R428,显示出更严重的RV肥大,右心室收缩压(RVSP)增加,心输出量受损,三尖瓣环面收缩期延长,总肺血管阻力指数明显增加[4]。体内药效试验表明,R428具有较长的血浆半衰期(75mg/kg时为13小时),并能有效地分布到组织中[5]。 在体内,小鼠(8周龄)用125mg/kg R428口服治疗,与肾炎B6小鼠肾脏中的T细胞数量相比,肾脏中的CD4+T细胞数量明显减少[6]。
| Cas No. | 1037624-75-1 | SDF | |
| 别名 | R-428;R 428;BGB324 | ||
| 化学名 | 1-(6,7-dihydro-5H-benzo[2,3]cyclohepta[2,4-d]pyridazin-3-yl)-3-N-[(7S)-7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]-1,2,4-triazole-3,5-diamine | ||
| Canonical SMILES | C1CCN(C1)C2CCC3=C(CC2)C=C(C=C3)NC4=NN(C(=N4)N)C5=NN=C6C(=C5)CCCC7=CC=CC=C76 | ||
| 分子式 | C30H34N8 | 分子量 | 506.64 |
| 溶解度 | ≥ 25mg/mL in DMSO with gentle warming | 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 | 1.9738 mL | 9.8689 mL | 19.7379 mL |
| 5 mM | 0.3948 mL | 1.9738 mL | 3.9476 mL |
| 10 mM | 0.1974 mL | 0.9869 mL | 1.9738 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。
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