gefitinib analogue v1801 induces apoptosis of t790m egfr-harboring lung cancer cells by up-regulation of the bh-3 only protein noxa吉非替尼类似物v1801凋亡的t790m egfr-harboring肺癌细胞的老年病bh-3只有蛋白质病因.pdfVIP

Gefitinib Analogue V1801 Induces Apoptosis of T790M EGFR-Harboring Lung Cancer Cells by Up-Regulation of the BH-3 Only Protein Noxa 1,3 2 4 1 1 2 2 Bo Zhang , Jiao Jiao , Ying Liu , Liang-Xia Guo , Bo Zhou , Gang-Qin Li , Zhu-Jun Yao *, Guang- Biao Zhou1* 1 Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China, 2 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, 3 Graduate University of the Chinese Academy of Sciences, Beijing, China, 4 The Shenzhen Key Laboratory of Gene and Antibody Therapy, Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, China Abstract Treatment of non-small cell lung cancer (NSCLC) with drugs targeting the epidermal growth factor receptor (EGFR), e.g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategies to overcome this resistance are therefore an urgent need. In this study, we synthesized a dozen of novel gefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-bromo-5-(trifluoromethyl) phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine (hereafter, V1801), triggered apoptosis of the NSCLC cells and overcame gefitinib-resistance in mice inoculated with NCI- H1975 cells. Though V1801 only moderately inhibited EGFR kinase activity, it markedly induced the expression of the BH3- only protein Noxa, and No