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）：该研究计划的目的是开发一种新型的潜在爱泼斯坦 - 巴尔病毒（EBV）感染的小分子抑制剂。 EBV是一种普遍存在的γ-疱疹病毒，已被世界卫生组织归类为人类致癌。 Vironika及其财团合作伙伴Wistar Institute和Fox Chase Chase Drivess Center，Inc。将开发出一种高度特异性且有效的EBV潜伏期抑制剂，Will为治疗EBV相关疾病提供了重要的治疗策略。潜在感染与多种人类恶性肿瘤有关，包括伯基特的淋巴瘤，鼻咽癌，霍奇金的淋巴瘤，胃癌和免疫细胞B-细胞淋巴瘤在免疫抑制期间。目前，尚无针对潜在感染的EBV特异性疗法，因此仍然不可能有效治疗或预防与EBV相关的疾病。潜在感染取决于病毒编码的蛋白质，该蛋白在病毒基因组的复制和维持中起作用。该蛋白质的遗传和生物学破坏会阻止病毒潜在感染和EBV依赖性B细胞生长。该蛋白的结合结构域在结构和生化上已经表征，并作为靶向小分子抑制EBV感染的理想分子。我们在主要的HTS屏幕中筛选了600,000多种化合物，并确定了一个铅。同时，我们使用基于碎片的方法发现了另一个铅分子。这些潜在客户具有很高的效力，选择性和宽阔的安全边缘。在此阶段2应用程序中，我们建议使用迭代过程进行铅优化。我们将综合类似物，在基于细胞和基于细胞的测定中测试其功效，并监控其责任。然后将测试铅类似物，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，并减轻毒性或其他负债。该第2阶段项目的目的是确定一个临床前候选者，E可以通过该候选者进行辅助研究，以进行第一阶段的第一阶段临床试验。