Drugging EBNA1 to Treat EBV-Associated Cancers

项目摘要 EBV潜伏感染每年导致约20万例新癌症。到目前为止，还没有EBV- 选择性有效地治疗EBV阳性肿瘤的特定治疗剂。所有人都知道 EBV肿瘤持续表达一种病毒核蛋白，EBNA1，这是维持 EBV基因组和促进受感染细胞存活。我们已经开发出高度选择性的，类似药物的 结合EBNA1并阻断其结合DNA的能力的小分子，维持EBV基因组，以及 促进宿主细胞存活。在这里，我们建议更好地了解通过 EBNA1 DNA结合的破坏导致肿瘤生长抑制，并利用这一信息来识别 合理组合用药，提高化疗疗效。我们建议加强 第一代EBNA1抑制剂通过附着蛋白酶体靶向分子的效力 (PROTACS)选择性地靶向EBNA1进行降解。最后，我们将利用新的 机械学数据显示，EBNA1作为ORIP特异的内切酶和解析酶发挥作用。 我们建议开发新的基于结构和机制的EBNA1抑制剂，使其能够增加 高效的癌症治疗所必需的效力。通过将这些战略整合到 了解EBNA1抑制的生长抑制反应(目标1)，以更好地发展理性 组合疗法的方法(目标2)和开发下一代分子 基于结构/机制的药物设计原则(目标3)，我们将推动EBNA1抑制剂用于 EB病毒相关恶性肿瘤及相关疾病的治疗。我们将测试最重要的 EBNA1是小分子抑制剂治疗EBV有效靶点的假说 癌症。这项建议的主要目标是了解肿瘤细胞对EBNA1的反应 抑制和提高EBNA1抑制剂治疗EBV相关癌症的疗效 非常有效。与这项提案相关的团队拥有独特的专业知识和强大的 合作历史，以执行这项提案的目标。总体而言，这些调查将 提供关于EBNA1如何在分子水平上发挥作用的基本见解，并将为 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.