新型 6-(2-取代乙酰氨基)-4-苯胺基喹唑啉类化合物作为 MCF-7 乳腺癌细胞中 EGFR-ERK 信号转导抑制剂。
Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells.
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, P.O. Box 11829, Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt.
出版信息
Eur J Med Chem. 2018 Jul 15;155:782-796. doi: 10.1016/j.ejmech.2018.06.024. Epub 2018 Jun 19.
Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC = 3 and 16 μM, respectively), compared to that of Erlotinib (IC = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed the anti-EGFR activity of compound 6n (IC = 0.037 μM). Finally, a molecular docking study showed the potential binding mode of 6n within the ATP catalytic binding site of EGFR, exhibiting similar binding mode to EGFR inhibitor Erlotinib.
表皮生长因子受体（EGFR）信号通路在多种恶性肿瘤的进展中具有重要作用，针对 EGFR 的小分子靶向药物的开发是设计抗肿瘤药物的一种重要策略。在此，我们报告了设计和合成了两系列 6-(2-取代乙酰氨基)-4-苯胺基喹唑啉（6a-x 和 13a-d）作为 EGFR 抑制剂。所有新合成的喹唑啉衍生物均在体外对 MCF-7（乳腺癌）和 HepG2（肝癌）细胞系进行了抗增殖活性评估。特别是，化合物 6n 对 MCF-7 和 HepG2 细胞系的抑制活性显著（IC=3 和 16 μM，分别），与厄洛替尼（IC=20 和 25 μM，分别）相比。在 MCF-7 细胞系中用 6n 进行 Western blot 分析表明，6n 具有双重抑制活性，可降低 EGFR 和 ERK 的磷酸化水平。此外，ELISA 测定证实了化合物 6n 的抗 EGFR 活性（IC=0.037 μM）。最后，分子对接研究表明 6n 能够在 EGFR 的 ATP 催化结合位点中潜在结合，其结合模式与 EGFR 抑制剂厄洛替尼相似。
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