Development of a Small Molecule Inhibitor for EBV Latent Infection

描述(申请人提供)：本研究计划的目标是开发一种新型的小分子抑制潜伏性EB病毒(EBV)感染的药物。EBV是一种普遍存在的伽玛疱疹病毒，已被世界卫生组织列为人类致癌物。Vironika与其财团合作伙伴Wistar Institute和Fox Chase化学多样性中心公司将开发一种高度特异和有效的EBV潜伏期抑制剂，这将为治疗EBV相关疾病提供一种重要的治疗策略。潜伏感染与多种人类恶性肿瘤有关，包括Burkitt淋巴瘤、鼻咽癌、霍奇金淋巴瘤、胃癌和免疫母细胞B细胞淋巴瘤。目前，还没有针对潜伏感染的EBV特异性治疗方法，因此仍然不可能有效地治疗或预防EBV相关疾病。潜伏感染依赖于病毒编码的蛋白质，该蛋白质在病毒基因组的复制和维护中发挥作用。这种蛋白的遗传和生物破坏阻止了病毒潜伏感染和依赖EBV的B细胞生长。该蛋白的结合域已被结构和生化鉴定，是靶向抑制EBV感染的理想小分子分子。我们已经在HTS的主屏幕上筛选了60多万种化合物，并确定了一条线索。与此同时，我们使用基于片段的方法发现了另一种铅分子。这些引线具有很高的效力、选择性和广泛的安全裕度。在此阶段2应用程序中，我们建议使用迭代流程来优化销售线索。我们将合成类似物，在病毒和细胞检测中测试它们的有效性，并监测它们的ADME风险。然后将测试铅类似物，以确定小鼠模型的药代动力学特性、毒性和疗效。对于每一轮，我们将优化化学类型的疗效和效力，并减轻毒性或其他风险。这个第二阶段项目的目标是确定一个临床前候选人，e可以与其一起进行IND-Enabling研究，以进入第一阶段的第一人临床试验。

DESCRIPTION (provided by applicant): The goal of this research program is to develop a novel small molecule inhibitor of latent Epstein-Barr Virus (EBV) infection. EBV is a ubiquitous gamma- herpesvirus that has been classified by the World Health Organization as a human carcinogen. Vironika, with its consortium partners the Wistar Institute and Fox Chase Chemical Diversity Center, Inc., will develop a highly specific and potent inhibitor of EBV latency that wil provide an important therapeutic strategy to treat EBV-associated diseases. Latent infection is associated with multiple human malignancies, including Burkitt's lymphoma, nasopharyngeal carcinomas, Hodgkin's lymphoma, gastric carcinomas, and immunoblastic B-cell lymphoma's during immunosuppression. Currently, no EBV-specific therapies exist that target latent infection, and therefore it remains impossible to effectively treat or prevent EBV-associated disease. The latent infection depends on a viral encoded protein which functions in the replication and maintenance of the viral genome. Genetic and biological disruption of this protein blocks viral latent infection and EBV-dependent B-cell growth. The binding domain of this protein has been characterized structurally and biochemically, and serves as an ideal molecule for targeted small molecule inhibition of EBV infection. We have screened over 600,000 compounds in our primary HTS screen and identified one lead. In parallel, we have discovered another lead molecule using a fragment-based approach. These leads have high potency, selectivity and wide safety margins. In this Phase 2 application, we propose to use an iterative process for lead optimization. We will synthesize analogues, test their efficacy in in viro and cell-based assays, and monitor their ADME liabilities. Lead analogs will then be tested to determine pharmacokinetic properties, toxicity and efficacy in a mouse model. For each round, we will optimize the efficacy and potency of the chemotypes and mitigate toxicity or other liabilities. The goal of this Phase 2 project is to identify one pre-clinical candidate with which e can perform IND-enabling studies to take into Phase 1 first-in-man clinical trials.