Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The Guangdong Provincial Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
Bioorg Med Chem. 2011 Aug 1;19(15):4529-35. doi: 10.1016/j.bmc.2011.06.022. Epub 2011 Jun 16.
Multi-target EGFR, VEGFR-2 and PDGFR inhibitors are highly useful anticancer agents with improved therapeutic efficacies. In this work, we used two virtual screening methods, support vector machines (SVM) and molecular docking, to identify a novel series of benzimidazole derivatives, 2-aryl benzimidazole compounds, as multi-target EGFR, VEGFR-2 and PDGFR inhibitors. 2-Aryl benzimidazole compounds were synthesized and their biological activities against a tumor cell line HepG-2 and specific kinases were evaluated. Among these compounds, compounds 5a and 5e exhibited high cytotoxicity against HepG-2 cells with IC₅₀ values at ∼2 μM. Further kinase assay study showed that compound 5a have good EGFR inhibitory activity and moderate VEGFR-2 and PDGFR inhibitory activities, while 5e have moderate EGFR inhibitory activity and slightly weaker VEGFR-2 and PDGFR inhibitory activities. Molecular docking analysis suggested that compound 5a more tightly interacts with EGFR and PDGFR than compound 5e. Our study discovered a novel series of benzimidazole derivatives as multi-target EGFR, VEGFR-2 and PDGFR kinases inhibitors.
多靶点 EGFR、VEGFR-2 和 PDGFR 抑制剂是具有改善治疗效果的高效抗癌药物。在这项工作中，我们使用了两种虚拟筛选方法，支持向量机 (SVM) 和分子对接，来鉴定一系列新型苯并咪唑衍生物，即 2-芳基苯并咪唑化合物，作为多靶点 EGFR、VEGFR-2 和 PDGFR 抑制剂。合成了 2-芳基苯并咪唑化合物，并评估了它们对肿瘤细胞系 HepG-2 和特定激酶的生物活性。在这些化合物中，化合物 5a 和 5e 对 HepG-2 细胞表现出高细胞毒性，IC₅₀ 值约为 2 μM。进一步的激酶测定研究表明，化合物 5a 对 EGFR 具有良好的抑制活性和适度的 VEGFR-2 和 PDGFR 抑制活性，而 5e 对 EGFR 具有适度的抑制活性和稍弱的 VEGFR-2 和 PDGFR 抑制活性。分子对接分析表明，化合物 5a 与 EGFR 和 PDGFR 的相互作用比化合物 5e 更紧密。我们的研究发现了一系列新型苯并咪唑衍生物，可作为多靶点 EGFR、VEGFR-2 和 PDGFR 激酶抑制剂。
