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]。