Peptide Based Antiagiogenic Antitumor Agent

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。到目前为止，只有少数几个 超过50种体内活性抗血管生成剂是小分子。又不许太多 从治疗的Vantage点来看，分子量试剂是更理想的。 我们的初步研究很重要，因为它们表明， 很可能我们将能够生产小分子抗血管生成剂。即， 我们已经i）发现了一种新的抗血管生成的抗肿瘤肽，betapep-25， 抑制小鼠肿瘤生长，ii）确定了关键结构元件 通过对betapep-25的SAR研究，以及iii）合理设计和制备 结构上更简单的betapep-25的基于二苯并呋喃的类似物， betapep-25的基本体外生物活性。这一重要机构 数据为计划中的研究提供了支持和动力， 以下目标： 目的1：鉴定二苯并呋喃类似物中的关键结构元件， 促进抗血管生成活性，然后增强这种活性。目标二： 研究体内抗血管生成和抗肿瘤的效果， 目的1中最有效的类似物的药代动力学性质。目标3： 增强来自目标2的最有效类似物的生物利用度。目标4： 研究联合抗血管生成治疗和化疗对 体内肿瘤此应用程序提供了一个全面和综合的计划 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。

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.