Pharmacological Evaluation of Novel Benzimidazole Derivatives and Its Clinical Applications

As angiogenesis is required for tumor growth and metastasis, suppressing angiogenesis is a promising strategy in limiting tumor progression. Vascular endothelial growth factor (VEGF), a critical pro-angiogenic factor, has thus become an attractive target for therapeutic interventions in cancer. A variety of approaches to inhibit VEGF activation of VEGFR are currently being assessed in clinical trials. These include soluble receptors that sequester VEGF, monoclonal antibodies targeting VEGF or VEGFR and small molecule inhibitors that inhibit protein kinase activity. These inhibitors including bevacizumab (AvastinR), sorafenib (NexavarR, BAY 43-9006) and sunitinib (SutentR, SU11248), inhibit VEGF-VEGFR signaling and have been approved by the United States Food and Drug Administration for indication of specific types of cancer. Small molecule benzimidazole derivatives, which have widely pharmacologically active, have been reported to be a key template and have the potential for the development of novel drugs such as anti-cancer, anti-angiogenic, analgesic and anti-inflammatory drugs. In an effort to discover more potent VEGF–VEGFR inhibitors, we evaluated a series of benzimidazole derivatives. To identify its anti-angiogenesis effects, VEGF-A-induced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs) will be accomplish. Ex vivo study such as VEGF-A-induced microvessel sprouting from aortic rings and in vivo studies including matrigel plug assay, tumor xenograft model, and lung metastasis model will be performed. Furthermore, we will explore its mechanisms on blocking VEGF-VEGFR2 signaling pathway. In addition, structure-activity relationship studies will be performed using computer modeling. On the other hand, recent studies indicated that some new series of benzimidazole derivatives with the anti-inflammatory activities have been noted. Here we screen a serious of benzimidazole derivatives to find a novel compound with anti-inflammatory effect, and explore its mechanisms. In addition, established two sepsis mouse model, LPS-induced endotoxemia mouse model and cecal ligation-induced sepsis mouse model, to explore the anti-sepsis effects of new benzimidazole compound. In this program, we will investigate the anti-angiogenesis effects and underlying mechanism of novel benzimidazole compound, to find a potential drug candidate for developing anti-angiogenic agent in the field of cancer and angiogenesis-related diseases. On the other hand, look for new anti-inflammatory agent in developing novel lead compound for anti-sepsis therapy.