COMBINATORIAL CHEMISTRY APPROACHES TO TARGETING CELL CYCLE REGULATORS

针对细胞周期调节因子的组合化学方法

• 批准号: 6223459
• 负责人: ANDREW D HAMILTON
• 金额: $ 12.1万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6223459
• 关键词: active sites; antineoplastics; binding sites; cell cycle; cell growth regulation; combinatorial chemistry; cyclin dependent kinase; drug design /synthesis /production; drug discovery /isolation; enzyme activity; enzyme inhibitors; genetic library; peptide analog; protein binding; protein sequence; protein tyrosine kinase; transcription factor

The primary aims of project 1 will be to develop new approaches for generating structural diversity in bioactive molecules and to target these compound libraries to critical targets in cell cycle control pathways. Our overriding theme will be to take peptide sequences or protein domains that have been identified either from knowledge of the biological target or from screening of phage display libraries and, by systematic application of novel combinatorial methods, to reduce them to highly potent, bioavailable and in vivo active anti-tumor agents. To do this we will develop several approaches to the facile generation of large combinatorial libraries of potentially active compounds and then apply each of these to the identification of lead structures for disruption of thee key steps in cell cycle control; receptor tyrosine kinase (CDK) function, signal transducers, and activators of transcription (STAT) signaling and cyclin dependent kinase (CDK) activity. Our approach to RTK inhibitors will exploit two strategies involving the design of protein surface binding agents and the construction of libraries of small heterocyclic derivatives of 2-phenylsulfenylindole. In the STAT area we will use solid phase parallel synthesis to prepare libraries of peptidomimetics that block the SH-2 domain of STAT3. With the CDKs we will develop libraries of mimics of key helical domains on the surface of the natural inhibitors, p16 and p21, as well as small heterocyclic derivatives that compete with ATP for binding to the enzyme active site. Screening of the libraries against these key steps in the cell cycle signaling pathways will be carried out in collaboration with Projects 2, 3, and 4. Our primary focus will be the identification and optimization of novel inhibitors for RTKs (including platelet derived growth factor receptor, epidermal growth factor receptor and ErbB2), the STAT family of proteins (with particular focus on STAT3) and the three principal cyclin dependent kinases (CDK2, CDK4 and CDK6).

项目1的主要目的是开发新方法来生成生物活性分子中的结构多样性，并将这些化合物库靶向细胞周期控制途径的关键目标。我们的压倒性主题是服用从了解生物靶标的知识或噬菌体显示库的筛选以及通过系统地应用新型组合方法来鉴定的肽序列或蛋白质结构域，以将其降低到具有高度有效，可生物利用和体内活性抗肿瘤剂。为此，我们将开发几种方法，以使潜在活跃化合物的大型组合文库的易于生成，然后将它们应用于识别铅结构，以破坏细胞周期控制中的关键步骤；受体酪氨酸激酶（CDK）功能，信号换能器和转录信号传导和细胞周期蛋白依赖性激酶（CDK）活性的活化剂。我们对RTK抑制剂的方法将利用涉及蛋白质表面结合剂设计的两种策略，以及构建2-苯基磺酰基的小杂环衍生物的库。在STAT区域，我们将使用固相并行合成来制备阻断STAT3 SH-2域的肽仪的库。使用CDK，我们将开发自然抑制剂p16和p21表面上关键螺旋结构域的模拟库以及与ATP竞争的小杂环衍生物，以结合酶的活性位点。将与项目2、3和4合作进行细胞周期信号通路中的这些关键步骤的筛查。我们的主要重点将是对RTK的新型抑制剂的识别和优化（包括血小板衍生的生长因子受体，血小板生长因子，表皮生长因子受体和ERB2），以及蛋白质的统计量（ct Cycrient），以及三个princion2 cycin cytin（cy）（cy）。 CDK4和CDK6）。