title: Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors.
abstract: 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.
authors: 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.
authors: Yunqi
authors: Y
authors: Li
authors: Chunyan
authors: C
authors: Tan
authors: Chunmei
authors: C
authors: Gao
authors: Cunlong
authors: C
authors: Zhang
authors: Xudong
authors: X
authors: Luan
authors: Xiaowu
authors: X
authors: Chen
authors: Hongxia
authors: H
authors: Liu
authors: Yuzong
authors: Y
authors: Chen
authors: Yuyang
authors: Y
authors: Jiang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2