Design, synthesis and antitumor activity of 4-indazolylpyrimidine derivatives as EGFR inhibitors.

IF 3.9 2区 化学 Q2 CHEMISTRY, APPLIED
Ting Yang, Xiaoling He, Ting Wu, Wenqiang Zhu, Zhiwu Long, Yi Le
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引用次数: 0

Abstract

To overcome T790M mutation, a novel series of 4-indazolypyrimidine derivatives were developed as novel EGFR inhibitors employing a scaffold hopping drug design strategy. The biological activities of the target compounds were evaluated against two tumor cell lines (A431 and NCI-H1975), normal cell 2BS and EGFRT790M/L858R kinase. The results indicated that the majority of the compounds exhibited promising antitumor activity and low toxicity. Specifically, compounds 4e and 4s displayed the highest efficacy, with IC50 values of 0.55 μM and 0.47 μM, respectively. Moreover, compounds 4e and 4s demonstrated exceptional activity against EGFRT790M/L858R, with IC50 values of 12.04 and 28.79 nM. Additionally, further studies revealed that compounds 4e and 4s could induce apoptosis in NCI-H1975 cells and arrest the cells in the G2/M phase. Molecular docking studies revealed that compounds 4e and 4s could interact closely with EGFR. These findings lay the groundwork for further investigation of compounds 4e and 4s as potential EGFR inhibitors.

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来源期刊
Molecular Diversity
Molecular Diversity 化学-化学综合
CiteScore
7.30
自引率
7.90%
发文量
219
审稿时长
2.7 months
期刊介绍: Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;
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