Abstract C105: Preclinical evaluation of galectin-1 targeting antiangiogenic, antitumor peptidomimetics

We have showed previously that the peptide 33mer anginex targets galectin‐1 (gal‐1) thereby inhibiting tumor endothelial cell proliferation via anoikis and attenuating tumor angiogenesis and tumor growth. Gal‐1 binds β‐galactoside groups on various cell surface receptors and is highly upregulated in tumor‐activated endothelial cells. Differential stromal elevation of gal‐1 over the tumor parenchyma has been reported in several cancers, including cancer of the breast, colon, prostate and ovaries. The aim of the present study was to develop gal‐1 targeting anti‐angiogenic peptidomimetics and anti‐tumor clinical candidates for use in the management of human cancers. Based on structure‐activity relationships of anginex, a partial‐peptide mimetic was designed, using dibenzofuran (DBF) as a β‐turn mimetic to maintain the two key β‐strands and the bioactive amphipathic β‐sheet conformation of the peptide. The best DBF‐based compound 6DBF7 (13mer) inhibited tumor angiogenesis and tumor growth in vivo better than parent anginex. Subsequently, by substituting natural and non‐natural amino acids, new DBF‐based analogues were generated and tested in vitro. The analogs with improved anti‐angiogenic activity and pharmacokinetic profile were then tested in tumor mouse models in vivo. The pre‐clinical development of these novel anti‐angiogenic and anti‐cancer peptidomimetics will aid in the development of small‐molecule mimetics and subsequently hold great promise for the management of human cancers in the clinic. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C105.