SKLB1206, a Novel Orally Available Multikinase Inhibitor Targeting EGFR Activating and T790M Mutants, ErbB2, ErbB4, and VEGFR2, Displays Potent Antitumor Activity Both In Vitro and In Vivo
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.
Youli Pan Yong Xu Shan Feng Shidong Luo Renlin Zheng Jiao Yang Lijiao Wang Lei Zhong Han-Yu Yang Bing-Lin Wang Yang Yu Jingjing Liu Zhixing Cao Xiaoyan Wang Pan Ji Zerong Wang Xin Chen Shuang Zhang Yu-Quan Wei Sheng-Yong Yang
State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,West China Medical School,S State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,West China Medical School,S
国内会议
成都
英文
952-962
2015-05-01（万方平台首次上网日期，不代表论文的发表时间）