Design, synthesis, and biological evaluation of novel amino acid-Osimertinib conjugates as potential EGFR inhibitors

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2026-01-01 Epub Date: 2025-11-07 DOI:10.1016/j.bmc.2025.118482

Hong-Ning Men , Peng-Fei Gu , Zheng Li , Yue Yu , Lin An , Ling Zhang , Tong-Hui Huang , You-Guang Zheng

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Abstract

In this study, a series of novel amino acid-conjugated Osimertinib scaffold derivatives were designed and synthesized as EGFR (T790M/L858R) mutations inhibitors. Notably, compound 10a potently inhibited EGFR (IC₅₀ = 0.046 μM) and displayed anti-proliferative activities against mutant non-small cell lung cancer cells (H1975 IC₅₀: 1.619 μM). Furthermore, compound 10a down-regulated the phosphorylation of EGFR, ERK and AKT in a dose-dependent manner in H1975 cells. At 5 μM, 10a suppressed p-ERK and p-AKT levels to 38 % and 40 % of control in H1975 cells, respectively. Cell cycle analysis revealed that compound 10a inhibited the proliferation of cells by inducing cell cycle arrest in the G1 phase. Molecular modeling indicated that compound 10a exhibited a binding mode analogous to that of Osimertinib. Overall, these results demonstrate the potential of 10a as an anticancer agent warranting further development.

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新型氨基酸-奥西替尼偶联物作为潜在EGFR抑制剂的设计、合成和生物学评价。

本研究设计并合成了一系列新型氨基酸偶联奥西替尼支架衍生物，作为EGFR （T790M/L858R）突变抑制剂。值得注意的是，化合物10a对EGFR有抑制作用（IC50 = 0.046 μM），对突变型非小细胞肺癌细胞有抑制增殖作用（H1975 IC50: 1.619 μM）。此外，化合物10a在H1975细胞中以剂量依赖的方式下调EGFR、ERK和AKT的磷酸化。在5 μM下，10a抑制H1975细胞中p-ERK和p-AKT水平分别为对照组的38%和40%。细胞周期分析显示，化合物10a通过诱导细胞周期阻滞在G1期来抑制细胞增殖。分子模拟表明，化合物10a具有与奥西替尼类似的结合模式。总的来说，这些结果表明10a作为抗癌药物的潜力值得进一步开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.