Development of a Small Molecule Inhibitor for EBV Latent Infection

EBV潜伏感染小分子抑制剂的研制

基本信息

批准号：
8857367
负责人：
Mark E McDonnell
金额：
$ 75万
依托单位：
VIRONIKA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8857367
关键词：
ADME Study Acyclovir Address Advanced Development Animal Model Animals B-Cell Lymphomas B-Lymphocytes Back Biochemical Biological Biological Assay Biological Availability Burkitt Lymphoma Carcinogens Cell Line Cell Proliferation Cells Central Nervous System Lymphoma Chemicals Clinical Trials Collaborations DNA-Directed DNA Polymerase Data Development Dose Drug Kinetics EBV-associated disease EBV-associated malignancy Ensure Epstein-Barr Virus Infections Epstein-Barr Virus latency Exhibits Foscarnet Foxes Genetic Goals Growth Health Herpesviridae Hodgkin Disease Human Human Herpesvirus 4 Immunosuppression In Vitro Incidence Individual Industry Infection Inhibitory Concentration 50 Lead Link Luciferases Lymphoma Lymphomagenesis Lymphoproliferative Disorders Maintenance Malignant Neoplasms Metabolic Methods Monitor Mus Nasopharynx Carcinoma Nuclear Antigens Pathology Pharmaceutical Chemistry Pharmaceutical Preparations Pharyngeal Carcinoma Phase Plasma Proteins Probability Process Property Protein Binding Protein Binding Domain Proteins Research Safety Stomach Carcinoma T-Cell Lymphoma Testing The Wistar Institute Therapeutic Toxic effect Toxicology Transplant Recipients Validation Viral Viral Genome Viral Proteins World Health Organization Xenograft Model analog base bioluminescence imaging cell growth cell transformation clinical practice drug candidate efficacy testing gammaherpesvirus immunosuppressed improved in vivo indexing inhibitor/antagonist killings latent infection man meetings mouse model novel pre-clinical prevent programs small molecule success tumor growth viral DNA

项目摘要

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.

描述（由申请人提供）：该研究计划的目标是开发一种新型小分子潜伏性 Epstein-Barr 病毒（EBV）感染抑制剂。 EBV 是一种普遍存在的γ-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 Chemical Diversity Center, Inc. 将开发一种高度特异性和有效的 EBV 潜伏期抑制剂，这将为治疗 EBV 相关疾病提供重要的治疗策略。潜伏感染与多种人类恶性肿瘤相关，包括伯基特淋巴瘤、鼻咽癌、霍奇金淋巴瘤、胃癌和免疫抑制期间的免疫母细胞B细胞淋巴瘤。目前，尚无针对潜伏感染的 EBV 特异性疗法，因此仍然不可能有效治疗或预防 EBV 相关疾病。潜伏感染取决于病毒编码的蛋白质，该蛋白质在病毒基因组的复制和维持中发挥作用。这种蛋白质的遗传和生物学破坏可阻止病毒潜伏感染和 EBV 依赖性 B 细胞生长。该蛋白的结合域已在结构和生化方面得到表征，可作为靶向小分子抑制 EBV 感染的理想分子。我们在初级 HTS 筛选中筛选了超过 600,000 种化合物，并确定了一种先导化合物。与此同时，我们使用基于片段的方法发现了另一种先导分子。这些先导化合物具有高效力、选择性和广泛的安全裕度。在此第 2 阶段应用中，我们建议使用迭代过程进行先导化合物优化。我们将合成类似物，测试它们在体外和细胞分析中的功效，并监测它们的 ADME 责任。然后将测试先导类似物，以确定小鼠模型中的药代动力学特性、毒性和功效。对于每一轮，我们将优化化学型的功效和效力，并减轻毒性或其他责任。该第二阶段项目的目标是确定一种临床前候选药物，可以利用该候选药物进行 IND 支持研究，以进入第一阶段首次人体临床试验。