Development of a Small Molecule Inhibitor for EBV Latent Infection

EBV潜伏感染小分子抑制剂的研制

• 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
• 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

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）：本研究项目的目标是开发一种新型小分子抑制剂，用于治疗潜伏性EB病毒（EBV）感染。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.将开发高度特异性和有效的EBV潜伏期抑制剂，其将提供治疗EBV相关疾病的重要治疗策略。潜伏性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性B细胞淋巴瘤。目前，不存在靶向潜伏感染的EBV特异性疗法，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持中起作用。这种蛋白质的遗传和生物破坏阻断病毒潜伏感染和EBV依赖性B细胞生长。该蛋白的结合结构域已在结构和生物化学上表征，并且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60万种化合物，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范围。在此第2阶段应用中，我们建议使用迭代过程进行潜在客户优化。我们将合成类似物，测试其在体内和细胞为基础的测定的疗效，并监测其ADME负债。然后将测试铅类似物以确定小鼠模型中的药代动力学性质、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II期项目的目标是确定一种临床前候选药物，以便进行IND使能研究，以纳入I期首次人体临床试验。