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期，并进入M期，只发生在细胞， 正确、准确地执行关键的预备活动。的 细胞周期检查点功能障碍的后果是不受控制的生长， 基因组不稳定性和癌症发展。一个重要的检查点， 正常细胞生长是限制点，发生在中/晚期 细胞周期的G1期。最近的研究结果表明，mTOR蛋白， 作为抗增殖药物雷帕霉素的靶点， 某些癌细胞中的G1进展。此外，很明显， p53缺陷型肿瘤细胞表达一种异常的DNA损伤激活的 这是一个检查点，可以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 为开发新型抗癌药物提供了丰富的靶点来源， 剂.本项目的主要目标是：（1）实施一个屏幕 用于mTOR激酶活性的新型抑制剂，和（2）开发基于细胞的 p53缺陷肿瘤中异常G2检查点抑制剂的筛选 细胞这些筛选将用于从大量的， 化学多样性库，并通过使用铅优化 组合化学，以及与其他组分的协同作用 关于NCDDG一系列二级检测和工程细胞模型 将被用来评估选择性和活动的命中从 主要屏幕该项目的总体目标是通过 NCDDG，作为抗癌剂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.