Peptide Based Antiagiogenic Antitumor Agent

基于肽的抗血管生成抗肿瘤剂

• 批准号: 6873740
• 负责人: KEVIN H. MAYO
• 金额: $ 29.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873740
• 关键词: analog; angiogenesis inhibitors; antineoplastics; arginine; benzofurans; cisplatin; combination chemotherapy; cyclophosphamide; drug design /synthesis /production; laboratory mouse; melanoma; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; ovary neoplasms; peptides; pharmacokinetics

DESCRIPTION (provided by applicant): Control of angiogenesis is an attractive possibility for controlling cancer. Consequently, antiangiogenic compounds have considerable potential as therapeutic agents. To date, only a few of the more than fifty in vivo-active antiangiogenics are small molecules. Yet low molecular weight agents are more desirable from a therapeutic vantage point. Our preliminary studies are significant because they show that it is quite likely we will be able to produce small molecule antiangiogenic agents. Namely, we have i) discovered a novel antiangiogenic antitumor peptide, betapep-25, that inhibits tumor growth in mice, ii) identified key structural elements through SAR studies of betapep-25, and iii) rationally designed and prepared a structurally simpler dibenzofuran-based analog of betapep-25 that maintains the essential in vitro biological activity of betapep-25. This significant body of data provides support and momentum for the planned studies that have the following aims: Aim 1:identify the key structural elements in the dibenzofuran analog that promotes antiangiogenic activity and then to enhance this activity. Aim 2: study the in vivo antiangiogenic and anti-tumor effectivenes and pharmacokinetic properties of the most potent analogs from Aim 1. Aim 3: enhance the bioavailability of the most potent analog from Aim 2. Aim 4: investigate use of combined antiangiogenic therapy and chemotherapy against tumors in vivo. This application presents a comprehensive and integrated plan that will enable us to capitalize on the exciting discovery of the antiangiogenic antitumor properties of betapep-25.

描述（由申请人提供）：血管生成的控制是一种有吸引力的 控制癌症的可能性。因此，抗血管生成化合物具有 作为治疗剂的巨大潜力。迄今为止，只有少数 比五十个体内活性抗血管生成学是小分子。虽然很低 从治疗性的有利位置，分子量剂更需要理想。 我们的初步研究很重要，因为它们表明这是很重要的 我们可能会产生小分子抗血管生成剂。即， 我们有i）发现了一种新型的抗血管生成抗肿瘤肽Betapep-25， 抑制小鼠的肿瘤生长，ii）确定了关键的结构元素 通过对Betapep-25的SAR研究以及III）理性设计和准备 结构上更简单的基于Dibenzofuran的BETAPEP-25的类似物 BETAPEP-25的必要体外生物学活性。这个重要的身体 数据为计划的研究提供了支持和势头 以下目的： 目标1：确定二苯并呋喃类似物中的关键结构元素 促进抗血管生成活性，然后增强该活性。目标2： 研究体内抗血管生成和抗肿瘤效应以及 AIM 1的最有效类似物的药代动力学特性。AIM3： 增强AIM 2中最有效的类似物的生物利用度。AIM 4： 调查使用抗血管生成疗法和化学疗法的使用 体内肿瘤。该应用程序提出了一个全面而综合的计划 这将使我们能够利用令人兴奋的发现 BETAPEP-25的抗血管生成抗肿瘤特性。