Peptide Based Antiagiogenic Antitumor Agent

描述(申请人提供)：控制血管生成是一项有吸引力的工作 控制癌症的可能性。因此，抗血管生成化合物 作为治疗剂有相当大的潜力。到目前为止，只有几个 50多种体内活性的抗血管生成药物都是小分子。但也很低 从治疗的角度来看，分子量剂更可取。 我们的初步研究是有意义的，因为它们表明 我们很有可能生产出小分子的抗血管生成剂。也就是说， 我们发现了一种新的抗血管生成抗肿瘤多肽Betapep-25， 抑制小鼠肿瘤生长，II)确定了关键的结构元素 通过对Betapep-25的合成孔径雷达研究，以及III)合理设计和制备了 结构更简单的基于二苯并呋喃的Betapep-25类似物，它保持了 Betapep-25的基本体外生物活性。这一重要的机构 数据为计划中的研究提供了支持和动力 以下目标： 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，进而增强这一活性。目标2： 体内抗血管生成和抗肿瘤作用的研究 来自目标1的最有效类似物的药代动力学特性。目标3： 提高来自目标2的最有效类似物的生物利用度。目标4： 联合应用抗血管生成治疗和化疗对肺癌的治疗作用 体内的肿瘤。该应用程序提供了一个全面和集成的计划 这将使我们能够利用这一令人兴奋的发现 倍他普-25的抗血管生成、抗肿瘤作用。

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.