Runx specific angiogenesis inhibitors

描述(由申请人提供)： 肿瘤生长需要新血管的募集(血管生成) 和转移。因此，血管生成抑制剂的发展 表示一种新方法，该方法可以提高现有 癌症治疗。矮小家族基因(Runx1、2、3)是转录因子 在包括内皮细胞(EC)在内的血管发育中起关键作用 迁移和干细胞募集以促进血管生成。RUNX DNA绑定 通过与CBF基因的产物结合而增强，该基因形成一种 具有三维(3D)结构的三聚体DNA结合络合物 已经确定了。计算机辅助合理药物设计(CADD)可用于 确定有可能成为治疗剂的化合物。 CAD数据库搜索包括筛选3D化学数据库以选择 与靶标上感兴趣的结合部位“匹配”的小分子 生物分子。然后获得识别出的小分子并对其进行 以实验化验来选择那些具有适当生物学特性的 活动。使用商业上可获得的化合物数据库避免了 需要化学合成，从而促进活性物质的鉴定 化合物。我们的假设是RUNX介导的特异性抑制 转录激活会抑制EC的迁移和血管生成。我们的 目标是将CADD与Runt可用的3D结构相结合 鉴定具有与Run选择性结合的高潜力化合物。两者都有 Runt的DNA和CBF结合区将分别作为靶点。这个 选定的化合物将被获得并接受实验测试 使用分析方法确定具有所需的Run结合活性的化合物以 确认它们是矮子专属的拮抗剂。欧共体移民分析将 然后用于筛选具有生物活性的候选化合物。这些 方法是通过以下途径抑制血管生成的首批尝试之一 转录靶向。因为抑制了RUNX转录活性 应减少血管生成，对造血和实体瘤均有生长作用 依赖血液供应生存和生长的动物将受到抑制。这个 从这一应用开发的先导化合物也可以在 非癌症情况，如黄斑变性、动脉粥样硬化或 糖尿病视网膜病变，其中不受控制的血管生成是导致 病理学。

DESCRIPTION (provided by applicant): Recruitment of new blood vessels (angiogenesis) is required for tumor growth and metastasis. Therefore, the development of angiogenesis inhibitors represents a new approach that may increase the effectiveness of existing cancer treatments. Runt family genes (Runx1,2,3) are transcription factors that playa key role in vascular development including endothelial cell (EC) migration and stem cell recruitment to promote angiogenesis. Runx DNA binding is enhanced by association with the product of the Cbf gene which forms a trimeric DNA binding complex whose 3-dimensional (3D) structure has recently been determined. Computer-aided rational drug design (CADD) can be used to identify chemical compounds with the potential to become therapeutic agents. CADD database searching involves screening of a 3D chemical database to select small molecules that "fit" in the binding site of interest on the target biomolecule. The identified small molecules are then obtained and subjected to experimental assays to select those with the appropriate biological activity. Use of a database of commercially available compounds avoids the need for chemical synthesis, thereby facilitating the identification of active compounds. Our hypothesis is that specific inhibition of Runx-mediated transcriptional activation will inhibit EC migration and angiogenesis. Our goals are to use CADD, in combination with the available 3D structure of Runt to identify compounds with a high potential to bind selectively to Runt. Both the DNA and Cbf binding regions of Runt will be individually targeted. The selected compounds will be obtained and subjected to experimental testing using assays to identify compounds with the desired Runt-binding activities to verify that they are Runt-specific antagonists. An EC migration assay will then be used to screen candidate compounds for biological activity. These approaches are one of the first attempts to inhibit angiogenesis via transcriptional targeting. Since inhibiting Runx transcriptional activity should reduce angiogenesis, the growth of both hematopoietic and solid tumors that depend on a blood supply for survival and growth will be inhibited. The lead compounds developed from this application could also find utility in non-cancer situations, such as macular degeneration, atherosclerosis, or diabetic retinopathy, where uncontrolled angiogenesis is responsible for the pathology.