COMBINATORIAL CHEMISTRY APPROACHES TO TARGETING CELL CYCLE REGULATORS

项目1的主要目标是开发新的方法来产生生物活性分子的结构多样性，并将这些化合物文库定位于细胞周期控制途径的关键靶点。我们最重要的主题将是利用从生物学靶点知识或从噬菌体展示文库筛选中确定的肽序列或蛋白质结构域，并通过系统地应用新的组合方法，将它们减少为高效，生物可利用和体内活性的抗肿瘤药物。为此，我们将开发几种方法，以方便地生成潜在活性化合物的大型组合文库，然后将每种方法应用于识别破坏细胞周期控制中三个关键步骤的先导结构；受体酪氨酸激酶（CDK）功能，信号转导，转录（STAT）信号传导和细胞周期蛋白依赖性激酶（CDK）活性的激活因子。我们的RTK抑制剂方法将采用两种策略，包括设计蛋白质表面结合剂和构建2-苯基磺酰吲哚小杂环衍生物文库。在STAT领域，我们将使用固相平行合成来制备阻断STAT3的SH-2结构域的肽模拟物文库。利用CDKs，我们将开发天然抑制剂p16和p21表面关键螺旋结构域的模拟文库，以及与ATP竞争结合酶活性位点的小杂环衍生物。针对细胞周期信号通路中这些关键步骤的文库筛选将与项目2、3和4合作进行。我们的主要重点将是鉴定和优化新的rtk抑制剂（包括血小板衍生生长因子受体，表皮生长因子受体和ErbB2）， STAT家族蛋白（特别关注STAT3）和三种主要的周期蛋白依赖性激酶（CDK2， CDK4和CDK6）。

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).