AST-1306

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.

miR-551b regulates epithelial-mesenchymal transition and metastasis of gastric cancer by inhibiting ERBB4 expression.[Pubmed:28501849]

Oncotarget. 2017 Jul 11;8(28):45725-45735.

Epithelial-mesenchymal transition (EMT) is an important biological process that is characteristic of malignant tumor cells with metastatic potential. We investigated the role of miR-551b in EMT and metastasis in gastric cancer (GC). We found that low miR-551b levels were associated with EMT, metastasis and a poor prognosis in GC patients. Further, two GC cell lines, MNK45 and SGC7901, exhibited lower miR-551b levels than the GES normal stomach cell line. Exposing MNK45 and SGC7901 cells to TGF-beta1 resulted in cell morphology changes characteristic of EMT, which was confirmed by Western blot analysis demonstrating low E-Cadherin and high N-Cadherin and Vimentin levels. Treatment with miR-551b mimics inhibited these EMT changes as well as Transwell migration and invasiveness. We identified ERBB4 as a potential target of miR-551b based on patient data from the TCGA. ERBB4 was upregulated in GC specimens, and its high expression correlated with a poor prognosis of GC patients. Dual luciferase assays revealed that miR-551b directly inhibited ERBB4 by binding to its 3'UTR. Moreover, treatment with miR-551b mimics or the ERBB4 inhibitor AST-1306 inhibited EMT in the GC cell lines. Finally, nude mice xenografted with GC cancer cell lines expressing miR-551b mimics exhibited smaller tumors and longer survival than mice engrafted with control GC cancer cells. These data indicate that miR-551b inhibits EMT and metastasis in GC by inhibiting ERBB4. miR-551b and ERBB4 are thus potential therapeutic targets for the treatment of GC.

Allitinib (AST-1306) is an orally active and irreversible EGFR and ErbB2 inhibitor with IC50s of 0.5 and 3 nM, respectively. Allitinib also inhibits ErbB4 with an IC50 of 0.8 nM. Allitinib is an anilino-quinazoline compound and has anti-cancer activity.

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