A Proteomic Strategy for Inhibiting Cancer-Associated Enzymes

抑制癌症相关酶的蛋白质组学策略

基本信息

项目摘要

Cancer remains one of the most prevalent and life-threatening diseases for which effective treatments and cures are rare. The molecular properties special to metastativ carcinomas that support their motile and invasive behavior are complex and ill-defined. One generally accepted notion depicts hydrolytic enzymes, such as proteases and lipases, as critical mediators of the aggressive properties of metastatic tumors. To identify novel cancer-associated hydrolases, Cravatt and coworkers have developed a chemical proteomic strategy referred to as activity-based protein profiling (ABPP) the utilizes active site-directed probes to readout changes in hydrolase function directly in whole cell, issue, and fluid proteomes. In previous reseach efforts, multiple enzyme activities were identified, including several serine proteases and lipases, that were differentially expressed in several different tumor types. Many of these enzyme activities are uncharacterized proteins that may represent new targets for the diagnosis and treatment of cancer and other diseases. The goal of this proposal is to discover potent and selective chemical inhibitors of these novel cancer-associated hydrolases and then test the effects of specific inhibitors on cancer cell proliferation/invasion. In this application, we will apply an multidisciplinary approach, utilizing synthetic chemistry, functional proteomic, and cell biology techniques.
癌症仍然是最常见和最危及生命的疾病之一,有效的治疗和治愈方法很少。转移性癌支持其运动和侵袭行为的特殊分子特性是复杂和模糊的。一种普遍接受的概念描述了水解酶,如蛋白酶和脂肪酶,作为转移性肿瘤侵袭性的关键介质。为了确定新的癌症相关水解酶,Cravatt及其同事开发了一种称为基于活性的蛋白质图谱(ABPP)的化学蛋白质组学策略,该策略利用活性位点定向探针直接在整个细胞、问题和流体蛋白质组中读出水解酶功能的变化。在以前的研究中,鉴定了多种酶的活性,包括几种丝氨酸蛋白酶和脂肪酶,它们在几种不同的肿瘤类型中有差异表达。这些酶的许多活性都是未知的蛋白质,可能代表着癌症和其他疾病的诊断和治疗的新靶点。这项建议的目标是发现这些新的癌症相关水解酶的有效和选择性的化学抑制剂,然后测试特定的抑制剂对癌细胞增殖/侵袭的影响。在这项应用中,我们将应用多学科方法,利用合成化学、功能蛋白质组学和细胞生物学技术。

项目成果

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Professor Dr. Stephan A. Sieber其他文献

Professor Dr. Stephan A. Sieber的其他文献

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{{ truncateString('Professor Dr. Stephan A. Sieber', 18)}}的其他基金

Exploiting quorum sensing inhibition of the natural products fimbrolide and elegaphenone in gram-negative bacteria
利用群体感应抑制革兰氏阴性菌中的天然产物芬溴内酯和榄香酮
  • 批准号:
    358921956
  • 财政年份:
    2017
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Chemical-proteomic tools to monitor pyridoxal phosphorylation and its function as an enzyme cofactor in disease-related pathways
用于监测吡哆醛磷酸化及其作为疾病相关途径中酶辅因子的功能的化学蛋白质组学工具
  • 批准号:
    314976069
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Identification of chemical compounds to inhibit the caseinolytic protease ClpXP complex and evaluate their biological activity
抑制酪蛋白分解酶 ClpXP 复合物的化合物的鉴定并评估其生物活性
  • 批准号:
    282324388
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Protein targets of rugulactone and illudin S: An analysis of their function and mechanism of action
胡古内酯和隐球菌素 S 的蛋白质靶点:功能和作用机制分析
  • 批准号:
    233925483
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Research Grants
A chemical proteomic strategy to identify novel drug targets in Plasmodium falciparum and corresponding lead compounds for the development of new antimalarials
一种化学蛋白质组学策略,用于识别恶性疟原虫中的新药物靶标和相应的先导化合物,用于开发新型抗疟药
  • 批准号:
    192524457
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Identification, validation and functional characterization of targets of myxobacterial compounds with potential for pharmacological cancer treatment
具有药物癌症治疗潜力的粘细菌化合物靶标的鉴定、验证和功能表征
  • 批准号:
    187769183
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
    Research Units
Chemisch-proteomische Strategien zur Identifikation krankheitsassoziierter Enzyme in pathogenen Bakterien als neuartige Angriffsziele für Antibiotika
化学蛋白质组学策略识别病原菌中与疾病相关的酶作为抗生素的新靶标
  • 批准号:
    28198381
  • 财政年份:
    2006
  • 资助金额:
    --
  • 项目类别:
    Independent Junior Research Groups
Deciphering the structure activity relationship, mode of action and uptake of isonitrile antibiotics in Gram-negative bacteria
破译革兰氏阴性菌中异腈抗生素的结构活性关系、作用方式和摄取
  • 批准号:
    505074737
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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基于Trojan Horse strategy的新型药物递呈系统在肝癌射频消融中的应用
  • 批准号:
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Is inhibiting pili electrical conductivity a new anti-virulence strategy?
抑制菌毛导电性是一种新的抗毒策略吗?
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通过抑制针对 RBPJ 的 Hh/Notch 信号传导开发肺 NET 的新治疗策略
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