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: 8204733
• 负责人: Jun O. Liu
• 金额: $ 33.01万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204733
• 关键词: Affinity; Angiogenesis Inhibition; Angiogenesis Inhibitors; Antifungal Agents; Basic Science; Biological Assay; Blood Vessels; Cell Proliferation; Cell model; Chemistry; Clinical; Communities; Development; Endothelial Cells; FDA approved; Fibroblast Growth Factor 2; Future Generations; Human; Immunosuppressive Agents; Investigation; Libraries; Malignant Neoplasms; Mediating; Molecular; Mus; Names; Neoplasm Metastasis; Pathogenesis; Pharmaceutical Preparations; Phase II Clinical Trials; Play; Preclinical Drug Evaluation; Principal Investigator; Reagent; Research; Role; Specificity; T-Cell Activation; Toxic effect; Translations; Vascular Endothelial Growth Factors; angiogenesis; cancer therapy; combinatorial; drug efficacy; high throughput screening; human disease; improved; in vivo; inhibitor/antagonist; next generation; novel; programs; research study; 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（由申请人提供）：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发挥着重要作用。抑制血管生成是控制肿瘤生长和转移的有前途的策略。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，以促进开发用于治疗癌症的下一代血管生成抑制剂。在初步研究中，我们建立了一个主要包含 FDA 批准的临床药物的库，并通过内皮细胞增殖测定对其进行筛选。我们已经发现了几种有效的药物，包括免疫抑制剂和抗真菌药物。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 批准的药物以及已达到 II 期临床试验的药物，以确定其他血管生成抑制剂，并使该库可供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剂靶点在小鼠和人类 T 细胞激活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，识别免疫抑制剂靶点的新抑制剂，以降低现有药物的毒性。我们将通过实验验证该抗真菌药物在内皮细胞中的潜在靶点，并对该抗真菌药物进行SAR研究，试图制备亲和试剂来识别和验证其在内皮细胞中的靶点，提高药物抑制真菌感染的功效。血管生成和肿瘤生长。血管生成，即新血管的形成，在包括癌症在内的几种重要的人类疾病中发挥着重要作用。该申请的主要目标是从现有药物中发现和开发新的血管生成抑制剂，以加速基础研究成果转化为新的癌症治疗方法，并促进开发特异性更高、毒性更低的下一代抗血管生成药物。

项目成果

The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells.

抗真菌药物伊曲康唑可抑制内皮细胞中血管内皮生长因子受体 2 (VEGFR2) 的糖基化、运输和信号传导。

• 发表时间: 2011-12-23
• 作者: Nacev, Benjamin A;Grassi, Paola;Dell, Anne;Haslam, Stuart M;Liu, Jun O
• 通讯作者: Liu, Jun O

Synergistic inhibition of endothelial cell proliferation, tube formation, and sprouting by cyclosporin A and itraconazole.

环孢菌素 A 和伊曲康唑协同抑制内皮细胞增殖、管形成和出芽。

• 发表时间: 2011
• 影响因子: 3.7
• 作者: Nacev, Benjamin A;Liu, Jun O
• 通讯作者: Liu, Jun O

A calcineurin-independent mechanism of angiogenesis inhibition by a nonimmunosuppressive cyclosporin A analog.

非免疫抑制性环孢菌素 A 类似物抑制血管生成的不依赖钙调神经磷酸酶的机制。

• 发表时间: 2011-08
• 作者: Nacev, Benjamin A;Low, Woon;Huang, Zhennian;Su, Tina T;Su, Zhuang;Alkuraya, Hisham;Kasuga, Dan;Sun, Woong;Träger, Mario;Braun, Manfred;Fischer, Gunter;Zhang, Kang;Liu, Jun O
• 通讯作者: Liu, Jun O

Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation.

化学筛选可识别 FDA 批准的药物和诱导胰腺内分泌早熟分化的靶途径。

• 发表时间: 2011-11-29
• 影响因子: 11.1
• 作者: Rovira, Meritxell;Huang, Wei;Yusuff, Shamila;Shim, Joong Sup;Ferrante, Anthony A;Liu, Jun O;Parsons, Michael J
• 通讯作者: Parsons, Michael J

Identification of an old antibiotic clofoctol as a novel activator of unfolded protein response pathways and an inhibitor of prostate cancer.

鉴定出一种古老的抗生素氯福克酚作为未折叠蛋白反应途径的新型激活剂和前列腺癌的抑制剂。

• 发表时间: 2014-10
• 影响因子: 7.3
• 作者: Wang, Minghua;Shim, Joong Sup;Li, Ruo;Dang, Yongjun;He, Qingli;Das, Manisha;Liu, Jun O
• 通讯作者: Liu, Jun O