COMBINATORIAL CHEMISTRY APPROACHES TO TARGETING CELL CYCLE REGULATORS

项目1的主要目标是开发新的方法，用于产生生物活性分子的结构多样性，并将这些化合物库靶向细胞周期控制途径中的关键靶标。我们压倒一切的主题将是采取肽序列或蛋白质结构域，已确定无论是从知识的生物靶标或筛选噬菌体展示库，并通过系统应用新的组合方法，以减少他们的高度有效的，生物利用度和体内活性抗肿瘤剂。要做到这一点，我们将开发几种方法来轻松生成潜在活性化合物的大型组合库，然后将这些方法中的每一种应用于鉴定用于破坏细胞周期控制中的三个关键步骤的前导结构;受体酪氨酸激酶（CDK）功能，信号转导子和转录激活子（STAT）信号传导和细胞周期蛋白依赖性激酶（CDK）活性。我们的RTK抑制剂的方法将利用两种策略，涉及蛋白质表面结合剂的设计和2-phenylsulfenylindole的小杂环衍生物库的构建。在STAT领域，我们将使用固相平行合成来制备阻断STAT 3的SH-2结构域的肽模拟物文库。与CDK，我们将开发的天然抑制剂，p16和p21的表面上的关键螺旋结构域的模拟库，以及小的杂环衍生物，竞争与ATP的酶活性位点的结合。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识别和优化新型RTKs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ErbB 2），STAT蛋白家族（特别关注STAT 3）和三种主要的细胞周期蛋白依赖性激酶（CDK 2，CDK 4和CDK 6）。

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).