Dibenzofuran-based Anginex Mimetics that Target Galectin-1

描述：该申请是一项竞争性更新，重点开发6DBF7，一种新型的基于二苯并呋喃（DBF）的部分肽模拟心绞痛，作为一种抗血管生成和抗肿瘤药物，用于临床治疗人类癌症。抗血管生成化合物作为治疗药物具有相当大的潜力，正如最近在抗vegf抗体阿瓦斯汀的临床试验中所证明的那样。我们最近发现6DBF7的分子靶点，像亲本anginex一样，是半乳糖凝集素-1，一种肿瘤血管生成领域的新受体。由于半乳糖凝集素-1通过促进内皮细胞的粘附和迁移介导肿瘤血管生成，并且在人类肿瘤中被发现是高表达的，因此它是治疗干预的主要目标。因此，优化6DBF7作为半乳糖凝集素-1的有效治疗剂和拮抗剂构成了这一应用的基础。在这里，我们提出了一种综合的药物发现方法，包括设计、合成和评估新的6DBF7类似物，目的是：确定6DBF7与半乳糖凝集素-1复合物的核磁共振结构，并评估新的6DBF7类似物与半乳糖凝集素-1的结合；目的2：利用基于结构和重点文库的方法增强6DBF7的抗血管生成活性和半乳糖凝集素-1结合；目的3：研究从目的2中鉴定的6DBF7类似物的体内暴露和功效。这项申请提供了一个全面和综合的计划，将使我们能够利用令人兴奋的发现，即6DBF7作为半凝集素-1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，我们有能力实现这项研究的目标，并将该化合物沿着临床前途径推进到临床试验。

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.