R428|1037624-75-1|安捷凯

Background

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].

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]。

参考文献:

[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.

Protocol

Cell experiment [1]:
Cell lines	B-CPAP cell line(derived from human PTC cancer tissue)
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.
Reaction Conditions	0.5 μmol/L, 1 μmol/L, 2 μmol/L, 4 μmol/L; for 24 h
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]:
Animal models	NOD-SCID male mice
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.
Dosage form	50 mg/kg/day; i.p.
Applications	R428 alone significantly inhibited ESCC tumor growth compared to the vehicle; however, no synergistic effect with cisplatin was observed.
参考文献: [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. [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.

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