Peptide Based Antiagiogenic Antitumor Agent

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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.