Runx specific angiogenesis inhibitors

描述（由申请人提供）： 招募新血管（血管生成）是肿瘤生长所必需的 和转移。 因此，血管生成抑制剂的开发 这是一种新的方法，可以提高现有的 癌症治疗 Runt家族基因（Runx 1，2，3）是转录因子 在血管发育中起关键作用，包括内皮细胞（EC） 迁移和干细胞募集以促进血管生成。 Runx DNA结合 通过与Cbf基因的产物结合而增强， 三聚体DNA结合复合物，其三维（3D）结构最近被 确定了 计算机辅助合理药物设计（CADD）可用于 鉴定具有成为治疗剂潜力的化合物。 CADD数据库搜索包括筛选3D化学数据库， “适合”目标上感兴趣的结合位点的小分子 生物分子 然后获得鉴定的小分子， 进行实验分析，以选择那些具有适当生物学特性的 活动 使用市售化合物的数据库避免了 需要化学合成，从而促进活性物质的鉴定。 化合物. 我们的假设是特异性抑制Runx介导的 转录激活将抑制EC迁移和血管生成。 我们 我们的目标是使用CADD，结合现有的3D结构的Runt 以鉴定具有选择性结合Runt的高潜力的化合物。 两 Runt的DNA和Cbf结合区将被单独靶向。 的 将获得选定的化合物并进行实验测试 使用测定来鉴定具有所需Runt结合活性的化合物， 确认它们是Runt特异性拮抗剂。 EC迁移测定将 然后用于筛选具有生物活性的候选化合物。 这些 这些方法是通过以下途径抑制血管生成的最初尝试之一： 转录靶向。 因为抑制Runx转录活性 应该减少血管生成，造血和实体肿瘤的生长 依赖血液供应生存和生长的细胞会受到抑制。 的 由该应用开发的先导化合物也可用于 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糖尿病视网膜病变的原因。 病理

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.