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

基本信息

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
项目类别：
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&apos -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

项目摘要

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·霍普金斯药物库的屏幕中，用于内皮细胞增殖的抑制剂，一种抗真菌药物，伊曲康唑，被确定为一种新型血管生成抑制剂。较早的研究表明，伊曲康唑的抗血管生成作用的几种重要细胞活性，包括抑制内皮细胞周期T G1和MTOR信号通路。 Itraconazole在体外和体内的血管生成和肿瘤异种移植物的各种动物模型中还显示出显着的抗血管生成活性。此外，Itraconazole已作为肺，前列腺和皮肤癌的新治疗方法进行了多项人类临床研究，以及如何表现出明显的功效。使用Itraconazole的可点击光探针，已经确定了伊曲康唑的主要结合蛋白。初步研究表明，敲击新鉴定的伊曲纳氮酶结合蛋白导致内皮细胞中MTOR的抑制作用。此外，伊曲康唑结合蛋白下游的信号传导激酶也被认为是MTOR的负调节剂，也被Itraconazole激活。该应用将集中于新确定的伊曲康唑结合蛋白作为直接靶标的表征和验证，及其下游激酶是伊曲康唑的抗血管生成活性的关键介体。还将尝试获得Itracoanzole及其推定目标之间复合物的晶体结构。通过系统地改变Itraconazole的不同结构结构域来提高其抗血管生成效力，其溶解性，同时降低其对CYP3A3药物替代酶及其肝毒性的抑制作用，可以通过系统地改变Itraconazole的不同结构结构域来合成伊曲康唑的新类似物。希望该项目的成功完成将促进伊曲康唑和类似物的临床发展，这是下一代新机械性血管生成药物的下一代。

项目成果

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Jun O. Liu其他文献

Binding of thalidomide to alpha1-acid glycoprotein may be involved in its inhibition of tumor necrosis factor alpha production.

沙利度胺与 α1-酸性糖蛋白的结合可能参与其抑制肿瘤坏死因子 α 的产生。

DOI：
10.1073/pnas.93.15.7552
发表时间：
1996
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
B. Turk;Hongsi Jiang;Jun O. Liu
通讯作者：
Jun O. Liu