CANCER DRUG DISCOVERY: CELL CYCLE CONTROL TARGETS

本项目申请的总体目标是发现基于破坏异常细胞周期转导途径的抗癌药物。组合化学和噬菌体展示肽库将用于创建结构多样性，生化和基于细胞的检测将致力于肿瘤转化的关键目标分子事件。该提案的中心主题将集中在三个周期控制靶点：受体酪氨酸激酶（RTK），信号转导和转录激活因子（STAT）和周期蛋白依赖性激酶（CDK）。我们采用多学科的方法来实现总体目标，包括四个不同但互补的项目。项目1将利用来自噬菌体展示肽库的结构和分子信息以及肽命中来合成组合文库，这些组合文库将创建大量具有破坏RTK及其配体、STAT和CDK致癌信号传导潜力的化合物。项目2将使用项目1合成的肽点和组合文库来破坏生长因子与其RTK的结合、受体酪氨酸自磷酸化和RTK的致癌信号传导和转化。项目3将使用来自噬菌体展示文库和组合文库的肽命中来破坏STAT3二聚化、DNA结合活性并阻断STAT3致癌信号传导和细胞转化。项目4将使用项目1合成的噬菌体展示肽库和组合文库中的肽来抑制CDK4-cyclin D1和CDK2-cyclin A复合物的活性，并破坏CDK向下游效应物（如肿瘤抑制因子Rb）的信号传导。项目2、3和4评估的结构活性关系研究结果将反馈给项目1，进一步优化先导化合物，然后在RTK、STAT和/或CDK通路异常激活的人类肿瘤裸鼠中评估其抑制增殖、促进细胞凋亡和阻断生长的能力。本项目所描述的工作将增强我们对RTK， STAT和CDK在人类癌症中的作用的理解，并最终将导致发现新的抗癌药物，这将扩大人类肿瘤的范围，可以成功治疗。

The overall goal of this program project application is to discover anti- cancer drugs based on disrupting aberrant cell cycle transduction pathways. Combinatorial chemistry and phage display peptide libraries will be used to create structural diversity, and biochemical and cell-based assays will be devoted to target molecular events critical to neoplastic transformation. The central theme of this proposal will focus on three cycle control targets: receptor tyrosine kinases (RTK), signal transducers and activators of transcription (STAT) and cyclin-dependent kinases (CDK). Our multi-disciplinary approach to accomplish the overall goal consists of four distinct but complementary projects. Project 1 will use structural and molecular information and peptide hits from phage display peptide libraries to synthesize combinatorial libraries that will create a large number of compounds with the potential of disrupting RTK and their ligands, STAT and CDK oncogenic signaling. Project 2 will use peptide hits as well as combinatorial libraries synthesized by Project 1 to disrupt growth factor binding to their RTK, receptor tyrosine auto- phosphorylation and RTK oncogenic signaling and transformation. Project 3 will use peptide hits from phage display libraries, and combinatorial libraries to disrupt STAT3 dimerization, DNA binding activity and to block STAT3 oncogenic signaling and cell transformation. Project 4 will use peptides from phage display peptide libraries and combinatorial libraries synthesized by project 1 to inhibit the activities of CDK4-cyclin D1 and CDK2-cyclin A complexes and to disrupt CDK signaling to down-stream effectors such as the tumor suppressor Rb. Results from the structure activity relationship studies carried out evaluated by projects 2, 3 and 4 will be fed back to project 1 for further optimization of lead compounds which will then be evaluated for their ability to inhibit proliferation, promote apoptosis and block the growth in nude mice of human tumors where RTK, STAT and/or CDK pathways are aberrantly activated. The work described in this program project will enhance our understanding of the role of RTK, STAT and CDK in human cancer and ultimately will result in the discovery of novel anti-cancer drugs that will broaden the spectrum of human tumors that can be treated successfully.