文献类型：期刊文献

英文题名：Discovery of Pteridin-7(8H)-one-Based Irreversible Inhibitors Targeting the Epidermal Growth Factor Receptor (EGFR) Kinase T790M/L858R Mutant

作者：Zhou, Wei[1];Liu, Xiaofeng[1];Tu, Zhengchao[2,3];Zhang, Lianwen[2,3];Ku, Xin[4];Bai, Fang[5,6];Zhao, Zhenjiang[1];Xu, Yufang[1];Ding, Ke[2,3];Li, Honglin[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China;[3]Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Inst Chem Biol, Guangzhou 510530, Guangdong, Peoples R China;[4]Tech Univ Munich, Lehrstuhl Prote & Bioanalyt, D-85354 Freising Weihenstephan, Germany;[5]Dalian Univ Technol, Fac Chem Environm & Biol Sci & Technol, Dalian 116023, Peoples R China;[6]Dalian Univ Technol, Dept Engn Mech, State Key Lab Struct Anal Ind Equipment, Dalian 116023, Peoples R China

年份：2013

卷号：56

期号：20

起止页码：7821

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000326259900011)】；

基金：The research is supported in part by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (grant nos. 81222046, 21173076, 81102375, 21302054, 21236002, and 81230076), the Special Fund for Major State Basic Research Project (grant no. 2009CB918501), the Shanghai Committee of Science and Technology (grant nos. 11DZ2260600 and 12401900801), and the 863 Hi-Tech Program of China (grant no. 2012AA020308). H.L. is also sponsored by the Program for New Century Excellent Talents in University (grant no. NCET-10-0378) and the Shanghai Rising-Star Tracking Program (grant no. 13QH1401100).

语种：英文

摘要：The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7(8H)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, 3q and 3x, exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound 3x significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need.