NEW TRANSLATION INITIATION INHIBITORS FOR CANCER THERAPY

描述：（申请人的描述） 细胞周期检查点确保关键的细胞周期事件，包括 承诺进入 S 期和进入 M 期仅发生在以下细胞中 正确、准确地执行了关键的前期活动。的 细胞周期检查点功能障碍的后果是生长不受控制， 基因组不稳定性和癌症发展。一个重要的检查站 正常细胞生长是限制点，发生在中后期 细胞周期的 G1 期。最近的研究结果表明，mTOR（蛋白质） 抗增殖药物雷帕霉素的靶向作用在驱动 某些癌细胞的 G1 期进展。此外，已经明确的是 p53缺陷的肿瘤细胞表达异常的DNA损伤激活 检查点保护这些细胞免于进入灾难性的有丝分裂。 项目 #1 所基于的假设是检查点缺陷 代表了人类癌细胞的普遍异常，因此 为新型抗癌药物的开发提供丰富的靶点来源 代理。该项目的主要目标是（1）实现屏幕 寻找 mTOR 激酶活性的新型抑制剂，以及 (2) 开发基于细胞的 筛选 p53 缺陷肿瘤中异常 G 2 检查点的抑制剂 细胞。这些筛选将用于从大量的、 化学多样化的文库，并通过使用进行先导化合物优化 组合化学以及与其他成分的协作相互作用 NCDDG 的。一系列二次分析和工程细胞模型 将用于评估命中的选择性和活性 主屏幕。该项目的总体目标是通过 NCDDG，作为抗癌药物进行临床前测试的新药。

Description: (Applicant's Description) Cell cycle checkpoints ensure that critical cell cycle events, including commitment to enter S phase, and entryinto M phase, occur only in cells that have properly and accurately executed critical preliminary events. The consequences of cell-cycle checkpoint dysfunction are uncontrolled growth, genomic instability , and cancer development. An important checkpoint for normal cell growth is the restriction point, which occurs in mid/late G1-phase of the cell cycle. Recent results suggest that mTOR, the protein targeted by the antiproliferative drug, rapamycin, plays a key role driving G1 progression in certain cancer cells. In addition, it has become clear that p53-deficient tumor cells express an abnormal, DNA-damage activated checkpoint that protects these cells from entering a catastrophic mitosis. The hypothesis upon which Project #1 is based is that checkpoint defects represent a universal abnormality of human cancer cells, and therefore provide a rich source of targets for the development of novel anticancer agents. The major objectives of this project are (1)to implement a screen for novel inhibitors of mTOR kinase activity, and (2) to develop a cell-based screen for inhibitors of the abnormal G 2 checkpoint in p53-deficient tumor cells. These screens will be used to identify novel compounds from a large, chemically diverse library , and for lead optimization through the use of combinatorial chemistry, and collaborative interactions with other components of the NCDDG. A series of secondary assays and engineered cellular models will be used to assess the selectivity and activities of hits from the primary screens. The overarching goal of this project is to move, through the NCDDG, novel drugs for preclinical testing as anticancer agents.