文献类型：期刊文献

英文题名：Rational design and synthesis of 2,4-dichloro-6-methyl pyrimidine derivatives as potential selective EGFRT790M/L858R inhibitors for the treatment of non-small cell lung cancer

作者：Duan, Lei[1];Chu, Cilong[1];Huang, Xiaoling[1];Yao, Huizhi[1];Wen, Jie[1];Chen, Rui[1];Wang, Caolin[2];Tu, Yuanbiao[3];Lv, Qiaoli[4,6];Pan, Qingshan[1,5];Xu, Shan[1,5]

机构：[1]Jiangxi Sci & Technol Normal Univ, Jiangxi Prov Key Lab Drug Design & Evaluat, Nanchang, Jiangxi, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai, Peoples R China;[3]Jangxi Univ Tradit Chinese Med, Canc Res Ctr, Nanchang, Peoples R China;[4]Jiangxi Canc Hosp, Jiangxi Key Lab Translat Canc Res, Nanchang, Jiangxi, Peoples R China;[5]Jiangxi Sci & Technol Normal Univ, Sch Pharm, Jiangxi Prov Key Lab Drug Design & Evaluat, 605 Fenglin Rd, Nanchang 330013, Jiangxi, Peoples R China;[6]Jiangxi Canc Hosp, Jiangxi Key Lab Translat Canc Res, 519 Beijing East Rd, Nanchang 330029, Jiangxi, Peoples R China

年份：2024

卷号：357

期号：5

外文期刊名：ARCHIV DER PHARMAZIE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001173784200001)】；

基金：The authors gratefully acknowledge the generous support provided by The National Natural Science Foundation of China (21967009 and 22264015), The Distinguished Young Scholars program of the Natural Science Foundation of Jiangxi Province (20224ACB216015), the Natural Science Foundation of Jiangxi Province, China (20224BAB206001 and 20224BAB216112), and the Young top talent research project of Jiangxi Science and Technology Normal University (2022QNBJRC003).

语种：英文

外文关键词：docking; EGFR; T790M/L858R mutation; NSCLC; patient-derived xenograft

摘要：Many patients with non-small cell lung cancer (NSCLC) initially benefit from epidermal growth factor receptor (EGFR) targeted therapy. Unfortunately, varying degrees of resistance or side effects eventually develop. Overcoming and preventing the resistance and side effects of EGFR inhibitors has become a hot topic of research today. Based on the previous studies on AZD-9291, we designed and synthesized two series of 2,4-dichloro-6-methylpyrimidine derivatives, 19 compounds in total, as potential inhibitors of the EGFR kinase. The most promising compound, L-18, showed better inhibitory activity (81.9%) and selectivity against EGFR(T790M/L858R) kinase. In addition, L-18 showed strong antiproliferative activity against H1975 cells with an IC50 value of 0.65 +/- 0.06 mu M and no toxicity to normal cells (LO-2). L-18 was able to dose-dependently induce the apoptosis of H1975 cells and produced a cell-cycle-blocking effect, and it can also dose-dependently inhibit the migration and invasion of H1975 cells. L-18 also showed in vivo anticancer efficacy in H1975 cells xenograft mice. We also performed a series of in vivo and in vitro toxicological evaluations of compound L-18, which did not cause obvious injury in mice during administration. These results suggest that L-18 may be a promising drug candidate that warrants further investigation.