Development of an inhibitor of VEGF expression

VEGF表达抑制剂的开发

• 批准号: 6935501
• 负责人: Joseph M Colacino
• 金额: $ 71.9万
• 依托单位: PTC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935501
• 关键词: angiogenesis inhibitors; antineoplastics; athymic mouse; biomarker; drug design /synthesis /production; neoplasm /cancer blood supply; neoplastic growth; pharmacokinetics; posttranscriptional RNA processing; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Up-regulation of vascular endothelial growth factor (VEGF), a key factor for angiogenesis, is an important contributor to the pathogenesis of cancer. The abundance of VEGF is in large part controlled at the posttranscriptional levels by sequences in both the 5'- and 3'-untranslated regions (UTRs) of its mRNA. The 5'- UTR contains an internal ribosomal entry site (IRES) that mediates a unique, cap-independent mode of translation initiation. Under hypoxic conditions, cap-dependent translation is dramatically impaired and the translation of the VEGF mRNA occurs through its cap-independent IRES. Thus, even under severe hypoxic conditions, cells are capable of producing large amounts of VEGF resulting in angiogenesis to support further tumor growth. Using PTC's proprietary technology platforms, we have successfully identified a compound that selectively and potently inhibits the expression of VEGF post transcriptionally. In the Phase I of this grant, we proposed to (1) characterize the UTR-selectivity of these compounds, (2) perform medicinal chemistry lead optimization to improve potency, selectivity, and pharmaceutical properties, and (3) establish a pharmacodynamic assay to measure in vivo efficacy. We exceeded these goals, and have identified a compound that is potent, seletive, and orally active in vivo. Here, in Phase II, we propose the following: (1) Conduct efficacy studies in a number of tumor models to establish the spectra of tumor types, optimal dosing regimens, and combination therapies utilizing this agent. Efficacy and combination studies will focus on the following five indications: soft tissue fibrosarcom; glioblastoma; hormone sensitive breast cancer; gastric cancer; and ovarian cancer. (2) Conduct ADME studies and toxicology of the lead compound to enable and design the clinical trials. These studies will include both non-GLP as well as IND-enabling GLP studies. (3) CMC, (4) Further elucidate the mechanism of action, and (5) Preparationion and submission of IND to initiate Phase I trials establishing safety and proof-of-concept in humans.

描述（由申请人提供）：血管内皮生长因子（VEGF）的上调是血管生成的关键因素，是癌症发病机制的重要贡献者。 VEGF 的丰度在很大程度上在转录后水平上由其 mRNA 5'-和 3'-非翻译区 (UTR) 中的序列控制。 5'-UTR 包含一个内部核糖体进入位点 (IRES)，可介导独特的、与帽无关的翻译起始模式。在缺氧条件下，帽依赖性翻译显着受损，并且 VEGF mRNA 的翻译通过其帽非依赖性 IRES 进行。因此，即使在严重缺氧条件下，细胞也能够产生大量 VEGF，导致血管生成以支持肿瘤的进一步生长。利用 PTC 的专有技术平台，我们成功鉴定了一种化合物，可以选择性地、有效地抑制 VEGF 转录后表达。在本次资助的第一阶段，我们建议 (1) 表征这些化合物的 UTR 选择性，(2) 进行药物化学先导化合物优化以提高效力、选择性和药物特性，以及 (3) 建立药效学测定测量体内功效。我们超越了这些目标，并鉴定出一种在体内有效、具有选择性且具有口服活性的化合物。在此，在第二阶段，我们提出以下建议：（1）在多种肿瘤模型中进行疗效研究，以确定肿瘤类型谱、最佳给药方案和利用该药物的联合疗法。功效和联合研究将集中于以下五个适应症：软组织纤维肉瘤；胶质母细胞瘤；激素敏感性乳腺癌；胃癌；和卵巢癌。 (2) 对先导化合物进行 ADME 研究和毒理学研究，以启动和设计临床试验。这些研究将包括非 GLP 以及支持 IND 的 GLP 研究。 (3) CMC，(4) 进一步阐明作用机制，以及 (5) 准备并提交 IND，以启动在人体中建立安全性和概念验证的 I 期试验。