AST-1306

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.