文献类型：期刊文献

英文题名：Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

作者：Hao, Yongjia[1];Wang, Xia[1];Zhang, Tao[2];Sun, Deheng[1];Tong, Yi[1];Xu, Yuqiong[1];Chen, Haiyang[1];Tong, Linjiang[2];Zhu, Lili[1];Zhao, Zhenjiang[1];Chen, Zhuo[1];Ding, Jian[2];Xie, Hua[2];Xu, Yufang[1];Li, Honglin[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab Chem Biol, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn,Sch Pharm, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China

年份：2016

卷号：59

期号：15

起止页码：7111

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000381452600009)】；

基金：The research is supported in part by the Fundamental Research Funds for the Central Universities, the National Natural Science Foundation of China (Grants 21302054, 81222046, and 81230076) (Z.C., H.L.), the Shanghai Committee of Science and Technology (Grants 14431902100 and 13ZR1453100) (Y.X., Z.C.), the National Key Research and Development Program (Grant 2016YFA0502304), the National S&T Major Project of China (Grant 2013ZX09507004), and the Twelfth Five-Year National Science & Technology Support Program (Grant 2012BAI29B06) (H.L.). H.L. is also sponsored by Specialized Research Fund for the Doctoral Program of Higher Education (Grant 20130074110004), the Innovation Program of Shanghai Municipal Education Commission (Grant 13SG32), and Fok Ying Tung Education Foundation (Grant 141035).

语种：英文

摘要：EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound 9), we present a structure based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFR. Finally, the most representative compound 17d was identified. This work, demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFR(L858R/T790M) over EGFR(WT), which may play an important role in designing new classes of mutant-selective EGFR inhibitors.