Drugging EBNA1 to Treat EBV-Associated Cancers

药物 EBNA1 治疗 EBV 相关癌症

基本信息

  • 批准号:
    10185459
  • 负责人:
  • 金额:
    $ 58.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-15 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary EBV latent infection is responsible for ~200,000 new cancers per year. To date, there are no EBV- specific therapeutic agents that selectively and efficaciously treat EBV-positive tumors. All known EBV tumors consistently express one viral nuclear protein, EBNA1, that is required for maintaining the EBV genome and promoting infected cell survival. We have developed highly selective, drug-like small molecules that bind EBNA1 and block its ability to bind DNA, maintain EBV genomes, and promote host-cell survival. Here we propose to better understand the mechanism through which disruption of EBNA1 DNA binding leads to tumor growth inhibition, and use this information to identify rational combinatorial agents to enhance chemotherapeutic efficacy. We propose to enhance the potency of the first generation EBNA1 inhibitors by attaching proteasome targeting molecules (PROTACS) to selectively target EBNA1 for degradation. Finally, we will take advantage of new mechanistic data revealing that EBNA1 functions as an OriP-specific endonuclease and resolvase. We propose to develop new structure and mechanism-based inhibitors of EBNA1 that can increase potency necessary for highly efficacious cancer therapy. By integrating these strategies to understand the growth arrest response of EBNA1 inhibition (aim 1) to better develop rational approaches for combinatorial therapies (aim 2) and develop next generation molecule with structure/mechanism based drug design principles (aim 3), we will advance EBNA1 inhibitors for the treatment of EBV-associated malignancies and related-diseases. We will test the overarching hypothesis that EBNA1 is an effective target for small molecule inhibitors to treat EBV cancers. The major goal of this proposal is to understand the tumor cell response to EBNA1 inhibition and to enhance efficacy of EBNA1 inhibitors to treat EBV-associated cancers more efficaciously. The team associated with this proposal has the unique expertise and strong collaborative history to execute the aims of this proposal. Collectively, these investigations will provide fundamental insights into how EBNA1 functions at the molecular level and will lay the foundation for the development of new strategies to treat EBV cancers.
项目总结

项目成果

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PAUL M LIEBERMAN其他文献

PAUL M LIEBERMAN的其他文献

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{{ truncateString('PAUL M LIEBERMAN', 18)}}的其他基金

Project 4: Regulation of EBV Latency and Oncogenesis by Hypoxia
项目4:缺氧对EBV潜伏期和肿瘤发生的调节
  • 批准号:
    10714176
  • 财政年份:
    2023
  • 资助金额:
    $ 58.25万
  • 项目类别:
Epigenomic Drivers of EBV Epithelial Cancers
EB 病毒上皮癌的表观基因组驱动因素
  • 批准号:
    10627690
  • 财政年份:
    2023
  • 资助金额:
    $ 58.25万
  • 项目类别:
Targeting the Epigenetic and Metabolic Control of EBV-Epithelial Cancers
针对 EB 病毒上皮癌的表观遗传和代谢控制
  • 批准号:
    10627689
  • 财政年份:
    2023
  • 资助金额:
    $ 58.25万
  • 项目类别:
EBNA1 Inhibitor for Treatment of EBV-positive DLBCL
EBNA1 抑制剂用于治疗 EBV 阳性 DLBCL
  • 批准号:
    10719866
  • 财政年份:
    2023
  • 资助金额:
    $ 58.25万
  • 项目类别:
Administrative and Biostatistics
行政和生物统计学
  • 批准号:
    10627693
  • 财政年份:
    2023
  • 资助金额:
    $ 58.25万
  • 项目类别:
Epigenetic Regulation of Epstein-Barr Virus
EB 病毒的表观遗传调控
  • 批准号:
    10363894
  • 财政年份:
    2022
  • 资助金额:
    $ 58.25万
  • 项目类别:
Epigenetic Regulation of Epstein-Barr Virus
EB 病毒的表观遗传调控
  • 批准号:
    10550255
  • 财政年份:
    2022
  • 资助金额:
    $ 58.25万
  • 项目类别:
Drugging EBNA1 to Treat EBV-Associated Cancers - Diversity Supplement
使用 EBNA1 药物治疗 EBV 相关癌症 - Diversity Supplement
  • 批准号:
    10818976
  • 财政年份:
    2021
  • 资助金额:
    $ 58.25万
  • 项目类别:
Regulation of EBV Latency by Purine Metabolism and Signaling
通过嘌呤代谢和信号传导调节 EBV 潜伏期
  • 批准号:
    10298045
  • 财政年份:
    2021
  • 资助金额:
    $ 58.25万
  • 项目类别:
Regulation of EBV Latency by Purine Metabolism and Signaling
通过嘌呤代谢和信号传导调节 EBV 潜伏期
  • 批准号:
    10407656
  • 财政年份:
    2021
  • 资助金额:
    $ 58.25万
  • 项目类别:

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口服抗肿瘤药物的获取延迟
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