Abstract LB-3: Evidence that dibenzofuran based anti-angiogenic, anti-tumor peptidomimetics target galectin-1

Abstract

Abstract Galectins, named for their selective binding to ß-galactoside-containing glycans, play crucial roles in many physiological as well as pathological processes. Galectin-1 (gal-1) in particular, has been shown to be differentially elevated in tumor endothelial cells in several cancers including cancer of the breast, colon, prostate and ovaries. Gal-1 targeting 33mer peptide, Anginex, inhibits tumor endothelial cell proliferation via anoikis and attenuates tumor angiogenesis and tumor growth. Based on structure-activity relationships of anginex, partial-peptide mimetic were designed, using dibenzofuran (DBF) as a ß-turn mimetic to maintain the two key ß-strands and the bioactive amphipathic ß-sheet conformation of the peptide. The best DBF-based compound 6DBF7 (13mer) inhibited tumor angiogenesis and tumor growth in vivo better than parent anginex. Here we report on the optimization of the anti-angiogenic activity of 6DBF7 analogs in vitro, by substitution of natural and non-natural amino acids, and subsequently the antiangiogenic and anti-tumor effects of the most promising analogs in vivo. In addition, by using NMR spectroscopy and flow cytometry, we demonstrate that the lead 6DBF7 analogs interact with galectin-1 at a site near to its carbohydrate binding domain and by doing so can compete off galectin-1 from binding to ß-galactoside-containing glycans on the surface of cells in vitro. Overall, this research contributes to our ability to design pharmaceutical agents that target galectin-1 and thereby inhibit tumor growth and are potentially clinical candidates for use in the management of human cancers. This work was supported by NIH grant CA096090 to KHM Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-3. doi:1538-7445.AM2012-LB-3