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Anti-epidermal growth factor receptor(EGFR)treatment has been successfully applied in clinical cancer therapy.However,the clinical efficacy of first-generation reversible EGFR inhibitors,such as gefitinib and erlotinib,is limited by the development of drug-resistant mutations,including the gatekeeper T790M mutation and upregulation of alternative signaling pathways.Second-generation irreversible EGFR inhibitors that were designed to overcome the drug resistance due to the T790M mutation have thus far had limited success.Here,we report a novel reversible EGFR inhibitor,SKLB1206,which has potent activity against EGFR with gefitinibsensitive and-resistant(T790M)mutations.In addition,SKLB1206 has also considerable inhibition potency against some other related oncokinases,including ErbB2,ErbB4,and VEGF receptor 2(VEGFR2).SKLB1206 exhibited highly antiproliferative activity against a range of EGFR-mutant cell lines,including gefitinibsensitive and-resistant cell lines,and EGFR or ErbB2-overexpressing cell lines.SKLB1206 also showed a potent antiangiogenesis effect in vitro,in a zebrafish embryonic angiogenesis assay,and in an alginate-encapsulate tumor cell assay.In vivo,oral administration of SKLB1206 showed complete tumor regression in gefitinibsensitive HCC827 and PC-9 xenograft models and showed a considerable antitumor effect on the gefitinibresistant H1975 model as well as other EGFR/ErbB2-overexpressing or-dependent tumor models including A431,LoVo,and N87 established in athymic mice.SKLB1206 also showed a very good oral bioavailability(50.1%).Collectively,these preclinical evaluations may support clinical development of SKLB1206 for cancers with EGFR-activating/resistance mutations or EGFR/ErbB2 overexpressed.