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AST-1306 is a novel irreversible epidermal growth factor receptor inhibitor for EGFR and ErbB4 with IC50 of 0.5 and 0.8 nM, respectively. AST-1306 selectively inhibits the tyrosine kinase activities of ErbB2 with an IC50 of 3 nM. AST-1306 also potently prevents the EGFR T790M/L858R double mutant with an IC50 value of 12 nM. For this, AST-1306 is approximately 500-fold more potent than lapatinib. AST-1306 is more than 3000-fold selective for ErbB family kinases over other kinase families including PDGFR, KDR and c-Met. AST-1306 might covalently bind to specific amino acid residues of EGFR and ErbB2, AST-1306 significantly and concentration-dependently prevents the growth of HIH3T3-EGFR T790M/L858R cells. AST-1306 effectively suppresses EGFR phosphorylation in HIH3T3-EGFR T790M/L858R cells. Moreover, AST-1306 prevents the growth of NCI-H1975 cells expressing the EGFR T790M/L858R mutation in a concentration-dependent manner. AST-1306 blocks phosphorylation of EGFR and downstream pathways as well. In addition, AST-1306 dose-dependently and markedly inhibits EGF-induced EGFR phosphorylation in A549 cells. AST-1306 inhibits the phosphorylation of EGFR and ErbB2, and downstream signaling in human cancer cells including A549 cells, Calu-3 cells and SK-OV-3 cells. Twice daily oral administration of AST-1306 gives rise to a dramatic prevention of tumor growth in SK-OV-3 and Calu-3 xenograft models. In SK-OV-3 models, tumors almost completely disappears after treatment with AST-1306 for 7 days. In contrast, AST-1306 only slightly inhibits the growth of tumor in HO-8910 and A549 xenograft models. Therefore, the antitumor efficacy of AST-1306 is greater in ErbB2-overexpressing tumor models than in models expressing low levels of ErbB2. AST-1306 is well tolerate. In addition, oral administration of AST-1306 twice daily for 3 weeks dramatically suppresses the growth of tumor in the FVB-2/Nneu models. After treatment for 11 days, tumors almost completely disappears. The body weights of the mice reduces by less than 20% during treatment. AST-1306 has entered in a phase I clinical trial in the treatment of EGFR-overexpressing tumors.
| Cell Experiment | |
|---|---|
| Cell lines | Calu-3 and A-549 cell lines |
| Preparation method | Using the SRB (Sulforhodamine B) assay to evaluate cell (including Calu-3, A-549 cell line et al.) proliferation . Briefly, seeding cells into 96-well plates and grown for 24 hours. Then treating the cells with increasing concentrations of AST-1306 and grown for a further 72 hours. The medium remains unchanged until the completion of the experiment. Then fixing the cells with 10% precooled trichloroacetic acid (TCA) for 1 hour at 4 °C and staining for 15 min at room temperature with 100 μL of 4 mg/mL SRB solution in 1% acetic acid. Then removingthe SRB , and quickly rinsing the cells five times with 1% acetic acid. After cells are air-dried, protein-bound dye is dissolved in 150 μL of 10 mM Tris base for 5 min and measured at 515 nm using a multiwell spectrophotometer.Calculating the inhibition rate on cell proliferation as (1 - A515 treated/A515 control) × 100%. Obtaining the IC50 value by the Logit method and determining from the results of at least 3 independent tests. |
| Concentrations | 0.001-1 μM |
| Incubation time | 72 hours |
| Animal Experiment | |
|---|---|
| Animal models | Nude mice bearing SK-OV-3 xenograft tumors and SK-OV-3FVB-2/Nneu transgenic mouse |
| Formulation | 0.5% hydroxypropyl methylcellulose (HPMC), grinding with agate morta |
| Dosages | 25 mg/kg, 50 mg/kg and 100 mg/kg |
| Administration | p.o., twice daily |
| Molecular Weight | 621.08 |
| Formula | C24H18ClFN4O2 |
| CAS Number | 1050500-29-2 |
| Solubility (25°C) | DMSO 50 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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