Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors

基于嘌呤和香豆素的 Hsp90 抑制剂的开发和评价

基本信息

  • 批准号:
    7738659
  • 负责人:
  • 金额:
    $ 35.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-05-19 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The 90 kDa heat shock proteins are proving to be extraordinary cancer chemotherapeutic targets as evidenced by the fact that more than 20 clinical trials are currently in progress. Unfortunately, all of these trials are based upon N-terminal inhibitors, primarily geldanamycin- derived, which exhibit serious formulation, scheduling and dosing difficulties as these compounds induce Hsp's at the same concentration they induce client protein degradation. Previous studies by Neckers and coworkers determined that Hsp90 contains a C-terminal ATP binding site that bound coumarin antibiotics competitively versus ATP. Like N-terminal inhibitors, inhibitors of the C-terminal binding domain also cause the degradation of Hsp90-dependent client proteins required for tumor cell growth and proliferation. A major drawback of the coumarin antibiotics is that they bind weakly to Hsp90 (IC50 approximately 700 micromolar); however, recent studies by our group have led to compounds ~1000 fold more active than these natural products. Through SAR studies we have been able to identify functionalities important for Hsp90 inhibition and have learned how to modulate Hsp90 in ways not previously realized. Thus, we have developed compounds that induce Hsp's at low concentrations that refold denatured proteins as a new method to treat various neurodegenerative diseases. In contrast, we have constructed molecules that inhibit Hsp90 without inducing Hsp's, and therefore provide a mechanism by which to bypass difficulties observed with N-terminal inhibitors in the clinic. In this application we propose to further develop the anti-tumor agents based on a purine and CoMFA model developed in my laboratory that will aid in the construction of more efficacious and soluble inhibitors of the Hsp90 C-terminal binding site. In addition to our extraordinary preliminary in vivo studies, it is proposed to further investigate the most active compounds in additional in vivo models of cancer. As a consequence of these studies, we believe we can provide a new platform for which new drugs can be based or realized for the treatment of cancer via modulation of the Hsp90 protein folding machinery. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to attack multiple cancer-enabling enzymes by targeting a protein (Hsp90) that is responsible for folding them, as all proteins must be folded to become active. Although clinical trials are in progress for compounds that target Hsp90, they exhibit detrimental properties that are proving difficult to overcome. We have identified molecules that do not exhibit these deleterious properties and have proven to be exceptional in preliminary animal models of cancer. We plan to continue and develop these drugs.
描述(由申请人提供):90 kDa热休克蛋白被证明是非凡的癌症化疗靶点,如目前正在进行的20多项临床试验所证明的。不幸的是,所有这些试验都是基于N-末端抑制剂,主要是格尔德霉素衍生的,其表现出严重的配制、调度和给药困难,因为这些化合物在与它们诱导客户蛋白降解相同的浓度下诱导Hsp。Neckers和同事先前的研究确定Hsp 90含有C末端ATP结合位点,其与香豆素抗生素竞争性结合ATP。像N-末端抑制剂一样,C-末端结合结构域的抑制剂也引起肿瘤细胞生长和增殖所需的Hsp 90依赖性客户蛋白的降解。香豆素抗生素的一个主要缺点是它们与Hsp 90的结合较弱(IC 50约为700微摩尔);然而,我们小组最近的研究已经导致化合物的活性比这些天然产物高出约1000倍。通过SAR研究,我们已经能够识别对Hsp 90抑制重要的功能,并学会了如何以以前没有意识到的方式调节Hsp 90。因此,我们已经开发了在低浓度下诱导热休克蛋白重折叠变性蛋白的化合物,作为治疗各种神经退行性疾病的新方法。相比之下,我们已经构建了抑制Hsp 90而不诱导Hsp的分子,因此提供了一种机制,通过该机制可以绕过在临床中用N-末端抑制剂观察到的困难。在本申请中,我们建议进一步开发基于嘌呤和CoMFA模型的抗肿瘤药物,该模型在我的实验室中开发,这将有助于构建更有效和可溶性的Hsp 90 C-末端结合位点抑制剂。除了我们非凡的初步体内研究外,还建议在其他癌症体内模型中进一步研究最具活性的化合物。作为这些研究的结果,我们相信我们可以提供一个新的平台,通过调节Hsp 90蛋白折叠机制,可以基于或实现新的药物来治疗癌症。公共卫生相关性:该提案的目标是通过靶向负责折叠它们的蛋白质(Hsp 90)来攻击多种致癌酶,因为所有蛋白质都必须折叠才能变得活跃。尽管靶向Hsp 90的化合物的临床试验正在进行中,但它们表现出难以克服的有害特性。我们已经鉴定出不表现出这些有害特性的分子,并且在初步的癌症动物模型中被证明是例外的。我们计划继续开发这些药物。

项目成果

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Brian S J Blagg其他文献

Brian S J Blagg的其他文献

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{{ truncateString('Brian S J Blagg', 18)}}的其他基金

Engineering the Next Generation of Safer Hsp90 Inhibitors
设计下一代更安全的 Hsp90 抑制剂
  • 批准号:
    10587304
  • 财政年份:
    2023
  • 资助金额:
    $ 35.27万
  • 项目类别:
Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors
基于嘌呤和香豆素的 Hsp90 抑制剂的开发和评价
  • 批准号:
    9514012
  • 财政年份:
    2018
  • 资助金额:
    $ 35.27万
  • 项目类别:
Hsp90B in Bladder Cancer
膀胱癌中的 Hsp90B
  • 批准号:
    9922232
  • 财政年份:
    2018
  • 资助金额:
    $ 35.27万
  • 项目类别:
Optimization and Investigation of Cruentaren A analogs
Cruentaren A 类似物的优化和研究
  • 批准号:
    9454428
  • 财政年份:
    2018
  • 资助金额:
    $ 35.27万
  • 项目类别:
Optimization and Investigation of Cruentaren A analogs
Cruentaren A 类似物的优化和研究
  • 批准号:
    9902368
  • 财政年份:
    2018
  • 资助金额:
    $ 35.27万
  • 项目类别:
Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors
基于嘌呤和香豆素的 Hsp90 抑制剂的开发和评价
  • 批准号:
    9600723
  • 财政年份:
    2018
  • 资助金额:
    $ 35.27万
  • 项目类别:
Optimization and Investigation of Cruentaren A analogs
Cruentaren A 类似物的优化和研究
  • 批准号:
    10078544
  • 财政年份:
    2018
  • 资助金额:
    $ 35.27万
  • 项目类别:
New paradigms for Hsp90 inhibition
Hsp90 抑制的新范例
  • 批准号:
    9762054
  • 财政年份:
    2017
  • 资助金额:
    $ 35.27万
  • 项目类别:
New paradigms for Hsp90 inhibition
Hsp90 抑制的新范例
  • 批准号:
    10000886
  • 财政年份:
    2017
  • 资助金额:
    $ 35.27万
  • 项目类别:
New paradigms for Hsp90 inhibition
Hsp90 抑制的新范例
  • 批准号:
    9379940
  • 财政年份:
    2017
  • 资助金额:
    $ 35.27万
  • 项目类别:

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