Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors

被引：4

作者：

Hu, Xiuqin ^{[1
]}

Wang, Disha ^{[1
]}

Tong, Yi ^{[1
]}

Tong, Linjiang ^{[2
]}

Wang, Xia ^{[1
]}

Zhu, Lili ^{[1
]}

Xie, Hua ^{[2
]}

Li, Shiliang ^{[1
]}

Yang, You ^{[1
]}

Xu, Yufang ^{[1
]}

机构：

[1] East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai, Peoples R China

来源：

FRONTIERS IN CHEMISTRY | 2017年 / 5卷

关键词：

EGFR; tyrosine kinase inhibitors; anilinopyrtmidine; glycosides; carbohydrate-based drugs; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; ACQUIRED-RESISTANCE; MUTANT; AZD9291; T790M; DISCOVERY; POTENT; STRATEGIES; MUTATIONS;

D O I：

10.3389/fchem.2017.00101

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inhibitors for combating EGFR L858R/T790M mutant associated with drug resistance in the treatment of non-small cell lung cancer revealed that 3-N-acryloyl-5-O-anilinopyrimidine ribose derivative la possessed potent and specific inhibitory activity against EGER L858R/1790M over WT EGER. Based upon molecular docking studies of the binding mode between compound la and EGFR, the distance between the Michael receptor and the pyrimidine scaffold is considered as an important factor for the inhibitory potency and future design of selective EGFR tyrosine kinase inhibitors against EGFR L858R/T790M mutants.

引用

页数：10

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