Dibenzofuran-based Anginex Mimetics that Target Galectin-1

本申请是一项竞争性更新，重点开发一种新型的基于二苯并呋喃(DBF)的血管紧张素部分肽模拟物6DBF7，作为临床上用于人类癌症治疗的抗血管生成和抗肿瘤药物。抗血管生成化合物具有相当大的治疗潜力，最近在临床上用抗血管内皮生长因子抗体阿瓦斯丁证明了这一点。我们最近发现，6DBF7的分子靶点是Galectin-1，与亲本Anginex一样，Galectin-1是肿瘤血管生成领域的新受体。由于Galectin-1通过促进内皮细胞黏附和迁移来介导肿瘤血管生成，并且在人类肿瘤中高表达，因此它是治疗干预的主要靶点。因此，6DBF7作为Galectin-1的有效治疗剂和拮抗剂的优化为其应用奠定了基础。在这里，我们提出了一种综合的药物发现方法，涉及到新的6DBF7类似物的设计、合成和评估，其目的如下：目的1确定6DBF7与Galectin-1络合物的核磁共振结构，并评估新的6DBF7类似物与Galectin-1的结合；目的2利用基于结构的方法和基于集中文库的方法，增强6DBF7的抗血管生成活性和Galectin-1结合；目的3研究从AIM 2中筛选出的6DBF7类似物的体内暴露和有效性。这一应用提出了一个全面和综合的计划，使我们能够利用6DBF7作为Galectin-1拮抗剂的抗血管生成和抗肿瘤特性的令人兴奋的发现。基于我们广泛的初步结果，我们处于有利地位，能够实现本研究的目标，并沿着临床前途径推动该化合物进入临床试验。

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.