AC0010, an Irreversible EGFR Inhibitor Selectively Targeting Mutated EGFR and Overcoming T790M-Induced Resistance in Animal Models and Lung Cancer Patients

作者：Xu, Xiao^*; Mao, Long; Xu, Wanhong; Tang, Wei; Zhang, Xiaoying; Xi, Biao; Xu, Rongda; Fang, Xin; Liu, Jia; Fang, Ce; Zhao, Li; Wang, Xiaobo; Jiang, Ji; Hu, Pei; Zhao, Hongyun; Zhang, Li^*

来源：Molecular Cancer Therapeutics, 2016, 15(11): 2586-2597.

DOI：10.1158/1535-7163.MCT-16-0281

• TYROSINE KINASE INHIBITORS
• ACQUIRED-RESISTANCE
• GEFITINIB
• MUTATIONS
• RECEPTOR
• T790M
• AZD9291
• ERLOTINIB
• 1ST-LINE
• THERAPY

AC0010 is a pyrrolopyrimidine-based irreversible EGFR inhibitor, structurally distinct from previously reported pyrimidine-based irreversible EGFR inhibitors, such as osimertinib and rociletinib. AC0010 selectively inhibits EGFR-active and T790M mutations with up to 298-fold increase in potency compared with wild-type EGFR. In a xenograft model, oral administration of AC0010 at a daily dose of 500 mg/kg resulted in complete remission of tumors with EGFR-active and T790M mutations for over 143 days with no weight loss. Three major metabolites of AC0010 were tested and showed no wild-type EGFR inhibition or off-target effects, such as inhibition of IGF-1R. AC0010 is safe in non-small cell lung cancer (NSCLC) patients at a dose range between 50 and 550 mg once per day, and no hyperglycemia or other severe adverse effects were detected, such as grade 3 QT prolongation. The objective responses were observed in NSCLC patients with EGFR T790M mutation.

• 出版日期2016-11-1
• 单位中国医学科学院北京协和医院; 中山大学