Runx specific angiogenesis inhibitors

Runx 特异性血管生成抑制剂

• 批准号: 6623458
• 负责人: ANTONINO PASSANITI
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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 2004-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623458
• 关键词: angiogenesis inhibitors; cell migration; chemical information system; chemical structure function; chimeric proteins; drug screening /evaluation; gel mobility shift assay; intermolecular interaction; luciferin monooxygenase; recombinant proteins; reporter genes; tissue /cell culture; transcription factor; vascular endothelium

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.

描述（由申请人提供）： 肿瘤生长需要募集新血管（血管生成） 和转移。 因此，血管生成抑制剂的发展 代表一种新方法，可能会提高现有的有效性 癌症治疗。 Runt家族基因（Runx1,2,3）是转录因子 Playa在包括内皮细胞（EC）的血管发育中的关键作用 迁移和干细胞募集以促进血管生成。 Runx DNA结合 通过与形成A 三维（3D）结构的三聚DNA结合复合物最近具有 已确定。 计算机辅助理性药物设计（CADD）可用于 鉴定具有成为治疗剂的潜力的化学化合物。 CADD数据库搜索涉及筛选3D化学数据库以选择 在目标上“拟合”的小分子 生物分子。 然后获得并进行确定的小分子 进行实验测定，以选择具有适当生物学的人 活动。 使用市售化合物数据库避免 需要化学合成，从而促进活跃的鉴定 化合物。 我们的假设是对Runx介导的特定抑制作用 转录激活将抑制EC迁移和血管生成。 我们的 目标是将CADD与Runt的可用3D结构结合在一起 识别具有高潜力与Runt结合的高潜力的化合物。 两个都 RUNT的DNA和CBF结合区域将分别针对。 这 将获得选定的化合物并进行实验测试 使用测定来识别具有所需的runt结合活动的化合物 验证它们是runt特异性的拮抗剂。 EC迁移分析将 然后用于筛选候选化合物以进行生物活性。 这些 方法是通过 转录靶向。 由于抑制RUNX转录活性 应减少血管生成，造血和实体瘤的生长 这取决于血液供应的生存和生长。 这 该应用程序开发的铅化合物也可能在 非癌症情况，例如黄斑变性，动脉粥样硬化或 糖尿病性视网膜病，不受控制的血管生成负责 病理。