文献类型：期刊文献

英文题名：Design, Synthesis, and Biological Evaluation of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

作者：Hao, Yongjia[1,2];Lyu, Jiankun[1];Qu, Rong[3];Tong, Yi[1];Sun, Deheng[1];Feng, Fang[3];Tong, Linjiang[3];Yang, Tingyuan[1];Zhao, Zhenjiang[1];Zhu, Lili[1];Ding, Jian[3];Xu, Yufang[1];Xie, Hua[3];Li, Honglin[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]Guizhou Univ Chinese Med, Sch Pharm, Guiyang 550025, Guizhou, Peoples R China;[3]Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2018

卷号：61

期号：13

起止页码：5609

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000439006100011)】；

基金：The research is supported in part by the National Key Research and Development Program (grant 2016YEA0502304), the Shanghai Committee of Science and Technology (grant 14431902100), and the Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under grant no. U1501501. Honglin Li is also sponsored by National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals.

语种：英文

摘要：First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives were designed and synthesized, among which the most potent compound 20g not only demonstrated significant inhibitory activity and selectivity for EGFR(L8S8R/T790M) and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that 20g might be used as a promising lead compound for further structural optimization as potent and selective EGFR(L8S8R/T790M) inhibitors.