Dibenzofuran-based Anginex Mimetics that Target Galectin-1

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DESCRIPTION: This application is a competitive renewal focused on developing 6DBF7, a novel dibenzofuran (DBF)- based partial peptide mimetic of anginex, as an antiangiogenic and antitumor agent for use in the management of human cancer in the clinic. Antiangiogenic compounds have considerable potential as therapeutic agents, as has been recently demonstrated in the clinic with the anti-VEGF antibody Avastin. We recently discovered that the molecular target of 6DBF7, like parent anginex, is galectin-1, a novel receptor in the tumor angiogenesis field. Because galectin-1 mediates tumor angiogenesis by promoting endothelial cell adhesion and migration and is found to be highly expressed in human tumors, it is a prime target for therapeutic intervention. Therefore, optimization of 6DBF7 as an effective therapeutic agent and antagonist of galectin-1 forms the basis of this application. Here, we propose an integrated approach to drug discovery that involves the design, synthesis, and evaluation of new 6DBF7 analogs in the context of the following aims: Aim 1 Determine the NMR structure of 6DBF7 in complex with galectin-1 and assess binding of new 6DBF7 analogs to galectin-1; Aim 2 Enhance the antiangiogenic activity and galectin-1 binding of 6DBF7 using structure-based and focused library-based approaches; Aim 3 Investigate in vivo exposure and efficacy of selected analogs of 6DBF7 identified from Aim 2. This application presents a comprehensive and integrated plan that will enable us to capitalize on the exciting discovery of the antiangiogenic and antitumor properties of 6DBF7 as an antagonist of galectin-1 Based on our extensive preliminary results, we are well-positioned to achieve the Aims of this study and advance the compound along the pre-clinical pathway toward clinical trials.