School of Pharmacy, Fudan University, Shanghai, 201203, China.
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
Eur J Med Chem. 2018 May 25;152:298-306. doi: 10.1016/j.ejmech.2018.04.052. Epub 2018 Apr 27.
A series of novel 2,4-diarylaminopyrimidine derivatives of AZD9291 were discovered as L858R/T790M mutant selective epidermal growth factor receptor (EGFR) inhibitors. The majority of these compounds exhibited moderate to excellent EGFR T790 M/L858R inhibitory activities and comparable anti-proliferative activities against double mutant over-expressed NCI-H1975 cells to that of AZD9291. The most promising compounds 8a displayed an IC of 4.1 nM against EGFR L858R/T790M mutants. 8a also showed excellent cytotoxic effect against NCI-H1975 cells with an IC of 59 nM and 100-fold selectivity over wide-type EGFR over-expressed A431 cells. Compound 8a significantly inhibited tumor growth in NCI-H1975 xenograft models at a non-toxic dose. Docking study performed for 8a with ATP binding site of EGFR-TK showed the similar binding mode to that of AZD9291. All these results suggested that compound 8a was a potential mutant-selective EGFR inhibitor.
一系列新型的 AZD9291 2,4-二芳基嘧啶衍生物被发现为 L858R/T790M 突变选择性表皮生长因子受体（EGFR）抑制剂。这些化合物中的大多数表现出中等至优异的 EGFR T790M/L858R 抑制活性，并且对过表达双突变体的 NCI-H1975 细胞的抗增殖活性与 AZD9291 相当。最有前途的化合物 8a 对 EGFR L858R/T790M 突变体的 IC 为 4.1nM。8a 对 NCI-H1975 细胞也表现出优异的细胞毒性作用，IC 为 59nM，对过表达 WT EGFR 的 A431 细胞的选择性是 100 倍。化合物 8a 在非毒性剂量下显著抑制 NCI-H1975 异种移植模型中的肿瘤生长。对 8a 与 EGFR-TK 的 ATP 结合位点进行的对接研究表明，其结合模式与 AZD9291 相似。所有这些结果表明，化合物 8a 是一种潜在的突变选择性 EGFR 抑制剂。
