Studies of the Antifungal Drug Itraconazole As A Novel Inhibitor of Angiogenesis

抗真菌药物伊曲康唑作为新型血管生成抑制剂的研究

• 批准号: 8817767
• 负责人: Jun O. Liu
• 金额: $ 37.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8817767
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; ATP Synthesis Pathway; Adverse effects; Affinity Labels; Alkynes; Angiogenesis Inhibitors; Animal Model; Antifungal Agents; Binding; Binding Proteins; Biochemical; Biological Assay; Biological Availability; Biological Models; CYP3A4 gene; Calcium Channel; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cells; Chemicals; Clinic; Clinical; Clinical Research; Complex; Development; Diazomethane; Disease; Dominant-Negative Mutation; Drug Interactions; Endothelial Cells; Enzymes; FDA approved; Generations; Genetic; Hepatotoxicity; Human; Individual; Itraconazole; Knock-out; Libraries; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediator of activation protein; Methods; Mitochondria; Modification; Molecular; Molecular Target; Names; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Protein Isoforms; Proteins; Raptors; Resistance; Signal Pathway; Signal Transduction; Skin Cancer; Solubility; Stereoisomer; Structure; Structure-Activity Relationship; TSC2 gene; Testing; Toxic effect; Translations; Umbilical vein; VDAC1 gene; Validation; Voltage-Dependent Anion Channel; affinity labeling; analog; angiogenesis; base; cancer therapy; human FRAP1 protein; improved; in vitro activity; in vivo; inhibitor/antagonist; insight; interest; knock-down; lead-binding proteins; mTOR Signaling Pathway; mTOR inhibition; mutant; next generation; novel; public health relevance; small hairpin RNA; stereochemistry; tumor xenograft

DESCRIPTION (provided by applicant): In a screen of the Johns Hopkins Drug Library for inhibitors of endothelial cell proliferation, an antifungal drug, itraconazole, was identified as a novel inhibitor of angiogenesis. Earlier studies revealed several important cellular activities of itraconazole underlying its anti-angiogenic effect, including inhibition of endothelial cell cycle t G1 and mTOR signaling pathway. Itraconazole also showed remarkable anti-angiogenic activity in vitro and in various animal models of angiogenesis and tumor xenografts in vivo. Moreover, itraconazole has entered multiple Phase 2 human clinical studies as a new treatment of lung, prostate and skin cancer and how shown significant efficacy. Using a clickable photoaffinity probe of itraconazole, a major binding protein of itraconazole has been identified. Preliminary studies showed that knocking down of newly identified itraconazle-binding protein led to the inhibition of mTOR in endothelial cells. Furthermore, a signaling kinase downstream of the itraconazole-binding protein that is known to be a negative regulator of mTOR was also found to be activated by itraconazole. This application will be focused on the characterization and validation of the newly identified itraconazole-binding protein as a direct target and its downstream kinase as key mediator of the antiangiogenic activity of itraconazole. Attempts will also be made to obtain a crystal structure of the complex between itracoanzole and its putative target. New analogs of itraconazole will be synthesized by systematically altering the different structural domains of itraconazole to improve its anti-angiogenic potency, its solubility while decreasing its inhibition of CYP3A3 drug-metabolizing enzyme and its hepatotoxicity. It is hoped that the successful completion of the project will facilitate the clinical development of itraconazole and analogs as the next generation of a new mechanistic class of angiogenesis drugs.

描述（由申请人提供）：在约翰霍普金斯大学药物库的内皮细胞增殖抑制剂筛选中，抗真菌药物伊曲康唑被确定为 新型血管生成抑制剂。早期研究揭示了伊曲康唑具有抗血管生成作用的几个重要细胞活性，包括抑制内皮细胞周期 t G1 和 mTOR 信号通路。伊曲康唑在体外以及各种体内血管生成和肿瘤异种移植动物模型中也显示出显着的抗血管生成活性。此外，伊曲康唑作为肺癌、前列腺癌和皮肤癌的新疗法已进入多项2期人体临床研究，并显示出显着疗效。使用伊曲康唑的可点击光亲和探针，已鉴定出伊曲康唑的主要结合蛋白。初步研究表明，敲除新发现的伊曲康唑结合蛋白可抑制内皮细胞中的 mTOR。此外，伊曲康唑结合蛋白下游的信号激酶（已知是 mTOR 的负调节因子）也被发现被伊曲康唑激活。该应用将重点关注新鉴定的伊曲康唑结合蛋白作为直接靶点及其下游激酶作为伊曲康唑抗血管生成活性关键介质的表征和验证。还将尝试获得伊曲康唑与其假定目标之间的复合物的晶体结构。通过系统地改变伊曲康唑的不同结构域，将合成新的伊曲康唑类似物，以提高其抗血管生成效力、溶解度，同时降低其对 CYP3A3 药物代谢酶的抑制及其肝毒性。希望该项目的成功完成将促进伊曲康唑及其类似物作为下一代新机制类血管生成药物的临床开发。