Dibenzofuran-based Anginex Mimetics that Target Galectin-1

基于二苯并呋喃的 Anginex 模拟物，靶向 Galectin-1

• 批准号: 7322753
• 负责人: KEVIN H. MAYO
• 金额: $ 29.91万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322753
• 关键词: Amino Acid Sequence; Angiogenesis Inhibitors; Antibodies; Avastin; Binding; Biological; Biological Assay; Biological Availability; Cell Adhesion; Cells; Characteristics; Chemical Exposure; Chemicals; Chemistry; Chick Embryo; Clinic; Clinical Trials; Complex; Development; Dose; Drug Kinetics; Endothelial Cells; Evaluation; Exhibits; Galectin 1; Goals; Growth; Half-Life; Human; Lead; Libraries; Malignant Neoplasms; Mediating; Metabolic; Modification; Molecular Target; Mus; Oral; Organ; Parents; Pathway interactions; Peptides; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Positioning Attribute; Preparation; Process; Property; Research Personnel; Route; Structure; Therapeutic Agents; Therapeutic Intervention; Tumor Angiogenesis; Variant; absorption; analog; angiogenesis; antitumor agent; base; bevacizumab; design; dibenzofuran; drug discovery; improved; in vitro Assay; in vivo; migration; mimetics; novel; pre-clinical; programs; receptor; response; tumor

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.

描述：该应用是一种竞争性更新，重点是开发6DBF7，这是一种新型的Dibenzofuran（DBF） - 基于Anginex的部分肽，作为一种抗血管生成和抗肿瘤剂，用于在临床中用于人类癌症。抗血管生成化合物作为治疗剂具有相当大的潜力，正如抗VEGF抗体avastin在诊所中最近证明的那样。最近，我们发现，像父播种一样，6DBF7的分子靶标是Galectin-1，这是肿瘤血管生成场中一种新型受体。由于Galectin-1通过促进内皮细胞粘附和迁移来介导肿瘤血管生成，并发现在人类肿瘤中高度表达，因此它是治疗干预的主要靶标。因此，将6DBF7优化为有效的治疗剂和Galectin-1的拮抗剂构成了本应用的基础。在这里，我们提出了一种综合的药物发现方法，涉及以下目标的设计，合成和评估新的6DBF7类似物的设计，AIM 1确定与Galectin-1中的6DBF7的NMR结构，并评估新的6DBF7模拟的结合新6DBF7与Galectin-1的结合； AIM 2使用基于结构和集中库的方法，增强了6DBF7的抗血管生成活性和Galectin-1结合； AIM 3调查从AIM 2确定的6DBF7的选定类似物的体内暴露和功效。此应用程序提出了一项全面而综合的计划，该计划将使我们能够利用令人兴奋的抗血管生成和抗肿瘤特性的令人兴奋的发现，这是6DBF7的6DBF7作为基于我们的广泛的prectiral and Inters and preal-proposition and-apotiment of apotiment of apotiment of apointion and pos and proposity a的对象，我们的态度是良好的，我们的目标是良好的，我们的目标是及格。临床试验的临床前途径。