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: 7477905
• 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/7477905
• 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.

产品说明：该申请是一项竞争性更新，重点是开发6DBF 7，一种新型的基于二苯并呋喃（DBF）的心绞痛部分肽模拟物，作为抗血管生成和抗肿瘤药物，用于临床人类癌症的治疗。抗血管生成化合物作为治疗剂具有相当大的潜力，如最近在临床中用抗VEGF抗体Avastin所证明的。我们最近发现，6DBF 7的分子靶点与亲本anginex一样，是半乳糖凝集素-1，一种肿瘤血管生成领域的新型受体。由于半乳糖凝集素-1通过促进内皮细胞粘附和迁移介导肿瘤血管生成，并且发现其在人类肿瘤中高度表达，因此其是治疗干预的主要靶标。因此，6DBF 7作为半乳糖凝集素-1的有效治疗剂和拮抗剂的优化形成了本申请的基础。在这里，我们提出了一种药物发现的综合方法，该方法涉及新的6DBF 7类似物的设计、合成和评价，其目的如下：目的1确定与半乳糖凝集素-1复合的6DBF 7的NMR结构，并评估新的6DBF 7类似物与半乳糖凝集素-1的结合;目的2利用基于结构和基于文库的方法增强6DBF 7的抗血管生成活性和与galectin-1的结合;目的3研究从目的2鉴定的6DBF 7的所选类似物的体内暴露和功效。本申请提出了一个全面和综合的计划，这将使我们能够利用令人兴奋的发现6 DBF 7作为半乳糖凝集素-1的拮抗剂的抗血管生成和抗肿瘤特性。基于我们广泛的初步结果，我们处于有利地位，以实现本研究的目的，并沿着沿着临床前途径将化合物推向临床试验。