NEW TRANSLATION INITIATION INHIBITORS FOR CANCER THERAPY

描述：(申请人描述) 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阶段，并进入M阶段，只发生在 正确、准确地执行了关键的前期活动。这个 细胞周期检查点功能障碍的后果是不受控制的生长， 基因组的不稳定性和癌症的发展。一个重要的检查站 细胞正常生长是细胞生长的限制点，出现在细胞生长的中后期 细胞周期的G1期。最近的结果表明，mTOR，一种蛋白质 作为抗增殖药物的靶点，雷帕霉素在推动 某些癌细胞的G1期进展。此外，很明显， P53缺失的肿瘤细胞表达异常，DNA损伤被激活 保护这些细胞不进入灾难性有丝分裂的检查点。 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 探员们。该项目的主要目标是(1)实现一个屏幕 寻找新的mTOR激酶活性抑制剂，以及(2)开发一种基于细胞的 P53缺陷性肿瘤中异常G2检查点抑制物的筛选 细胞。这些筛子将被用来从一个大的， 化学多样性的文库，并通过使用 组合化学，以及与其他组件的协作交互 NCDDG的。一系列二次分析和工程化细胞模型 将用于评估来自 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试验的新药。

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.