Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs

现有药物中新型血管生成抑制剂的发现和研究

• 批准号: 7351352
• 负责人: Jun O. Liu
• 金额: $ 34.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351352
• 关键词: Affinity; Angiogenesis Inhibition; Angiogenesis Inhibitors; Animal Model; Antifungal Agents; Antineoplastic Agents; Azoles; B-Lymphocytes; Basic Science; Biological Assay; Biotin; Blood Vessels; Cell Cycle Arrest; Cell Proliferation; Cell model; Cell physiology; Chemistry; Clinical; Communities; Development; Endothelial Cells; Enzymes; Family; Fibroblast Growth Factor 2; Follow-Up Studies; Future Generations; Human; Immunosuppression; Immunosuppressive Agents; Inosine Monophosphate; Inosine Monophosphate Dehydrogenase Inhibitor; Investigation; Itraconazole; Knockout Mice; Lanosterol; Libraries; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Target; Mus; Mycophenolic Acid; Neoplasm Metastasis; Oxidoreductase; Pathogenesis; Pathologic Neovascularization; Pharmaceutical Preparations; Phase II Clinical Trials; Photoaffinity Labels; Play; Positioning Attribute; Preclinical Drug Evaluation; Protein Isoforms; Proteins; RNA Interference; Reagent; Research Personnel; Role; Screening procedure; Small Interfering RNA; Specificity; Structure; Subfamily lentivirinae; T-Cell Activation; T-Lymphocyte; Testing; Toxic effect; Translations; Validation; Vascular Endothelial Growth Factors; analog; angiogenesis; cancer therapy; combinatorial; drug efficacy; high throughput screening; human disease; improved; in vivo; inhibitor/antagonist; knockout animal; next generation; novel; research study; tumor; tumor growth

DESCRIPTION (provided by applicant): Angiogenesis, the formation of new blood vessels, plays an essential role in the pathogenesis of several important human diseases including cancer. Inhibition of angiogenesis is a promising strategy to control tumor growth and metastasis. The main objective of this application is to discover and develop new angiogenesis inhibitors from existing clinical drugs and to elucidate the molecular mechanisms of angiogenesis inhibition by two angiogenesis inhibitors previously discovered to facilitate the development of the next generation of angiogenesis inhibitors for the treatment of cancer. In preliminary studies, we have assembled a library of mostly FDA-approved clinical drugs and screened it in an endothelial cell proliferation assay. We have identified several potent hits including an immunosuppressant drug and an antifungal drug. We have further demonstrated the efficacy of both drugs in blocking VEGF- and bFGF- mediated angiogenesis in vivo. In this study, we propose to further expand the clinical drug library to include more FDA-approved drugs as well as those that have reached phase II clinical trials to identify additional inhibitors of angiogenesis and make the library available to the wider scientific community to screen in other cellular models. We will further characterize the function of the immunosuppressant target in both T cell activation and angiogenesis in mice and humans. We will attempt to identify new inhibitors for the immunosuppressant target to reduce the toxicity of the existing drug by a combination of combinatorial click chemistry and high-throughput screening. We will perform experiments to verify a potential target for the antifungal drug in endothelial cells and perform SAR studies on the antifungal drug in attempts to prepare affinity reagents to identify and validate its target in endothelial cells and to improve the efficacy of the drug for inhibition of angiogenesis and tumor growth. Angiogenesis, the formation of new blood vessels, plays an essential role in several important human diseases including cancer. The main objective of this application is to discover and develop new angiogenesis inhibitors from existing drugs to accelerate the translation of basic research findings into new cancer treatments and to facilitate the development of future generations of anti-angiogenic drugs with improved specificity and lower toxicity.

描述（申请人提供）：血管生成，即新血管的形成，在包括癌症在内的几种重要人类疾病的发病机制中起着至关重要的作用。抑制血管生成是一种很有前途的控制肿瘤生长和转移的策略。本申请的主要目的是从现有的临床药物中发现和开发新的血管生成抑制剂，并阐明先前发现的两种血管生成抑制剂抑制血管生成的分子机制，以促进用于治疗癌症的下一代血管生成抑制剂的开发。在初步研究中，我们已经建立了一个主要由fda批准的临床药物组成的文库，并在内皮细胞增殖试验中对其进行筛选。我们已经确定了几种有效的药物包括免疫抑制药物和抗真菌药物。我们进一步证明了这两种药物在体内阻断VEGF和bFGF介导的血管生成的功效。在这项研究中，我们建议进一步扩大临床药物库，包括更多fda批准的药物以及那些已经达到II期临床试验的药物，以确定更多的血管生成抑制剂，并使文库可用于更广泛的科学界筛选其他细胞模型。我们将进一步表征免疫抑制靶点在小鼠和人类T细胞活化和血管生成中的功能。我们将尝试通过组合点击化学和高通量筛选相结合的方法，为免疫抑制靶点寻找新的抑制剂，以降低现有药物的毒性。我们将通过实验验证抗真菌药物在内皮细胞中的潜在靶点，并对抗真菌药物进行SAR研究，试图制备亲和试剂，以鉴定和验证其在内皮细胞中的靶点，并提高药物抑制血管生成和肿瘤生长的功效。血管生成，即新血管的形成，在包括癌症在内的几种重要人类疾病中起着至关重要的作用。这项申请的主要目的是从现有药物中发现和开发新的血管生成抑制剂，以加速将基础研究成果转化为新的癌症治疗方法，并促进未来几代具有更高特异性和更低毒性的抗血管生成药物的开发。