Drugging EBNA1 to Treat EBV-Associated Cancers

项目摘要 EBV潜伏感染每年导致约200，000例新癌症。到目前为止，还没有EB病毒- 选择性和有效治疗EBV阳性肿瘤的特异性治疗剂。所有已知 EBV肿瘤始终表达一种病毒核蛋白EBNA 1，其是维持EBV感染所必需的。 EB病毒基因组和促进感染细胞存活。我们已经开发出了高选择性的，类似药物的 结合EBNA 1并阻断其结合DNA、维持EBV基因组的能力的小分子， 促进宿主细胞存活。在这里，我们建议更好地理解 EBNA 1 DNA结合的破坏导致肿瘤生长抑制，并使用此信息来鉴定 合理的组合药剂以增强化疗功效。我们建议加强 通过连接蛋白酶体靶向分子的第一代EBNA 1抑制剂的效力 （PROTACS）选择性靶向EBNA 1进行降解。最后，我们将利用新的 揭示EBNA 1作为OriP特异性内切核酸酶和解离酶发挥功能的机制数据。 我们建议开发新的EBNA 1结构和机制的抑制剂，可以增加 高效癌症治疗所必需的效力。通过整合这些策略， 了解EBNA 1抑制的生长停滞反应（目的1），以更好地制定合理的 组合疗法的方法（目标2），并开发下一代分子， 基于结构/机制的药物设计原则（目的3），我们将推进EBNA 1抑制剂， 治疗EBV相关的恶性肿瘤和相关疾病。我们将测试 假设EBNA 1是小分子抑制剂治疗EBV有效靶点 癌的该提案的主要目标是了解肿瘤细胞对EBNA 1的反应。 抑制和增强EBNA 1抑制剂治疗EBV相关癌症的功效 有效地。与此提案相关的团队拥有独特的专业知识和强大的 合作历史，以实现本提案的目标。这些调查将 为EBNA 1如何在分子水平上发挥作用提供了基本的见解，并将奠定 为开发治疗EBV癌症的新策略奠定了基础。

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.