An irreversible inhibitor of EGFR, HER2, and HER4
AST1306 is a novel inhibitor of EGFR and HER2 (IC50 = 0.5 nM and 3 nM respectively)
EGFR (epidermal growth factor receptor) is a cell-surface receptor tyrosine kinase. The receptor activation leads to dimerization and tyrosine autophosphorylation. It induces a cascade of downstream cellular responses such as modification in gene expression, cell proliferation and cytoskeletal rearrangement etc. HER2 is a member of the epidermal growth factor and is associated with breast and ovarian cancers.
AST1306 selectively blocked EGFR and HER2 kinase activities in a cell-free assay. The tyrosine kinase activity of EGFR mutant T790M/L858R was also inhibited by AST1306 in intact cell and cell-free assays. In addition, AST1306 attenuated the EGFR and HER2 phosphorylation and downstream substrates. [1]
In ErbB2-overexpressing xenograft and FVB-2/Nneu transgenic mouse model, AST1306 potently inhibited tumor growth. In SK-OV-3 xenograft model, AST1306 caused a quick and long-lasting (≥24h) inhibition of EGFR and HER2. [1]
Reference:
1. Xie H, Lin L, Tong L et al.? AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo. PLoS One. 2011;6(7):e21487.
Cell experiment: | Cells are seeded into 96-well plates and grown for 24 h. The cells are then treated with increasing concentrations of Allitinib (AST1306) and grown for a further 72 h. Cell proliferation is evaluated using the SRB (Sulforhodamine B) assay[1]. |
Animal experiment: | Mice: Mice are administered Allitinib (AST1306) at dosage of 100, 50 and 25 mg/kg twice daily and treated with lapatinib (50 mg/kg) as comparison. Tumors are measured twice a week in two dimensions, using a caliper, and the tumor volume is calculated according to the formula L×W×W/2[1]. |
参考文献: [1]. Xie H, Lin L, Tong L et al. AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo. PLoS One. 2011;6(7):e21487. | |
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