R428 (Synonyms: R-428;R 428;BGB324)

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.