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:
  • 金额:
    $ 37.06万
  • 依托单位:
  • 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

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筛选内皮细胞增殖抑制剂时,抗真菌药物伊曲康唑被鉴定为 新的血管生成抑制剂。早期的研究揭示了伊曲康唑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。伊曲康唑在体外和体内血管生成和肿瘤异种移植的各种动物模型中也显示出显著的抗血管生成活性。此外,伊曲康唑作为肺癌、前列腺癌和皮肤癌的新治疗方法已进入多项2期人体临床研究,并显示出显著的疗效。利用可点击的伊曲康唑光亲和探针,鉴定了伊曲康唑的主要结合蛋白。初步研究表明,敲低新鉴定的伊曲康那结合蛋白导致内皮细胞中mTOR的抑制。此外,伊曲康唑结合蛋白下游的信号激酶也被发现被伊曲康唑激活,该蛋白已知是mTOR的负调节剂。本申请将集中在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的关键介体的表征和验证上。还将尝试获得伊曲康唑与其假定靶点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来合成伊曲康唑的新类似物,以提高其抗血管生成效力、溶解度,同时降低其对CYP3A3药物代谢酶的抑制和肝毒性。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血管生成药物的临床开发。

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。
suppresses the oncogenic activity of YAP YAP complex - Genetic and pharmacological disruption of the TEAD
抑制 YAP YAP 复合物的致癌活性 - TEAD 的遗传和药理学破坏
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Y. Liu;Bo Huang;J. Shim;Qian Chen;Se;Robert A. Anders;Jun O. Liu;Duojia Pan
  • 通讯作者:
    Duojia Pan
Phase of the Cell Cycle 1 IL-2-Dependent T Cell Proliferation at the G Immunosuppressant, Inhibits Sanglifehrin A, a Novel Cyclophilin-Binding
细胞周期 1 阶段 IL-2 依赖性 T 细胞在 G 处增殖 免疫抑制剂抑制 Sanglifehrin A(一种新型亲环蛋白结合)
  • DOI:
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ling;Jun O. Liu
  • 通讯作者:
    Jun O. Liu
Selective inhibition of amino-terminal methionine processing by TNP-470 and ovalicin in endothelial cells.
TNP-470 和卵黄素在内皮细胞中选择性抑制氨基末端甲硫氨酸加工。
  • DOI:
  • 发表时间:
    1999
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Benjamin E. Turk;Eric C. Griffith;Susan M. Wolf;Klaus Biemann;Yie;Jun O. Liu
  • 通讯作者:
    Jun O. Liu
Girolline is a sequence context-selective modulator of eIF5A activity
吉罗啉是一种 eIF5A 活性的序列上下文选择性调节剂
  • DOI:
    10.1038/s41467-024-54838-2
  • 发表时间:
    2025-01-10
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Tilman Schneider-Poetsch;Yongjun Dang;Wakana Iwasaki;Mayumi Arata;Yuichi Shichino;Ali Al Mourabit;Celine Moriou;Daniel Romo;Jun O. Liu;Takuhiro Ito;Shintaro Iwasaki;Minoru Yoshida
  • 通讯作者:
    Minoru Yoshida

Jun O. Liu的其他文献

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{{ truncateString('Jun O. Liu', 18)}}的其他基金

Characterization of A Novel Proteasome Inhibitor
新型蛋白酶体抑制剂的表征
  • 批准号:
    10597711
  • 财政年份:
    2022
  • 资助金额:
    $ 37.06万
  • 项目类别:
Targeting Glucose Transporters Using Rapafucins
使用雷帕夫星靶向葡萄糖转运蛋白
  • 批准号:
    10335197
  • 财政年份:
    2020
  • 资助金额:
    $ 37.06万
  • 项目类别:
Targeting Glucose Transporters Using Rapafucins
使用雷帕夫星靶向葡萄糖转运蛋白
  • 批准号:
    10557907
  • 财政年份:
    2020
  • 资助金额:
    $ 37.06万
  • 项目类别:
Generation and Proteome-Wide Screening of Hybrid Combinatorial Libraries
混合组合文库的生成和全蛋白质组筛选
  • 批准号:
    8520275
  • 财政年份:
    2010
  • 资助金额:
    $ 37.06万
  • 项目类别:
Generation and Proteome-Wide Screening of Hybrid Combinatorial Libraries
混合组合文库的生成和全蛋白质组筛选
  • 批准号:
    8323364
  • 财政年份:
    2010
  • 资助金额:
    $ 37.06万
  • 项目类别:
Generation and Proteome-Wide Screening of Hybrid Combinatorial Libraries
混合组合文库的生成和全蛋白质组筛选
  • 批准号:
    8151102
  • 财政年份:
    2010
  • 资助金额:
    $ 37.06万
  • 项目类别:
Generation and Proteome-Wide Screening of Hybrid Combinatorial Libraries
混合组合文库的生成和全蛋白质组筛选
  • 批准号:
    7979320
  • 财政年份:
    2010
  • 资助金额:
    $ 37.06万
  • 项目类别:
Generation and Proteome-Wide Screening of Hybrid Combinatorial Libraries
混合组合文库的生成和全蛋白质组筛选
  • 批准号:
    8705479
  • 财政年份:
    2010
  • 资助金额:
    $ 37.06万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 37.06万
  • 项目类别:
Structure, Function and Inhibition of Human Methionine Aminopeptidases
人蛋氨酸氨基肽酶的结构、功能和抑制
  • 批准号:
    7835697
  • 财政年份:
    2008
  • 资助金额:
    $ 37.06万
  • 项目类别:

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