Targeting Cell Cycle Machinery For Cancer Therapy

针对癌症治疗的细胞周期机制

• 批准号: 7111098
• 负责人: E Premkumar Reddy
• 金额: $ 30.13万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7111098
• 关键词: affinity chromatography; athymic mouse; cell cycle; cell growth regulation; cell line; covalent bond; cyclin dependent kinase; drug screening /evaluation; enzyme activity; enzyme complex; enzyme substrate; gene expression; growth factor receptors; kinase inhibitor; laboratory mouse; laboratory rat; leukemia; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; paclitaxel; pharmacokinetics; phosphorylation; platelet derived growth factor; survivin

DESCRIPTION (provided by applicant): Cell cycle progression is regulated by cyclin-dependent kinases, which are critical for cell growth. Tumor development is often associated with genetic alterations in growth regulatory pathways leading to a loss of checkpoints that promotes cell cycle progression. Most normal cells differ from tumor cells with respect to their G1 checkpoint control, and this difference provides an approach for the development of therapeutic agents that discriminate between normal and tumor cells. In this application, we present data, which show the derivation of a novel group of small molecule kinase inhibitors that induce growth arrest of normal cells in the G1 phase of the cell cycle, while inducing a mitotic arrest of tumor cells. These compounds, termed as ON01 series inhibit the cyclin dependent kinases, CDK2 and CDK1, as well as PDGF Receptor. The ensuing result appears to be selective killing of tumor cell populations with little or no effect on normal cell viability. We propose experiments aimed at delineating their mechanism of action and their value as cancer therapeutics. The aims are: 1. To determine the kinetics of inhibition of CDK1 and CDK2 by ON01500 and ON013100; 2. To study the mechanism by which ON01 series block normal cell cycle progression in the G1 phase of the cell cycle; 3. To study the molecular consequences of CDK1 inhibition in tumor cells with respect to Survivin and Stathamin, which are known to play a critical role in the spindle assembly; 4. To carry out safety and bioavailability and efficacy studies with two candidate drugs, ON01500- DMG and ON013100-P, using MDR+ and MDR- tumor cell lines; and 5. To determine the in vitro and in vivo effects of ON013100 on hematopoietic cell growth and differentiation and determine whether 13100 can be used as a purging agent for human leukemia's.

描述（由申请人提供）：细胞周期进程受细胞周期蛋白依赖性激酶调节，这对细胞生长至关重要。肿瘤的发展通常与生长调节途径的遗传改变有关，导致促进细胞周期进展的检查点丢失。大多数正常细胞在 G1 检查点控制方面与肿瘤细胞不同，这种差异为开发区分正常细胞和肿瘤细胞的治疗剂提供了一种方法。在本申请中，我们提供的数据显示了一组新型小分子激酶抑制剂的衍生，这些抑制剂可诱导正常细胞生长停滞在细胞周期的 G1 期，同时诱导肿瘤细胞有丝分裂停滞。这些化合物被称为 ON01 系列，抑制细胞周期蛋白依赖性激酶、CDK2 和 CDK1 以及 PDGF 受体。由此产生的结果似乎是选择性杀死肿瘤细胞群，而对正常细胞活力几乎没有影响或没有影响。我们提出的实验旨在描述它们的作用机制及其作为癌症治疗的价值。目的是： 1. 确定ON01500和ON013100抑制CDK1和CDK2的动力学； 2、研究ON01系列在细胞周期G1期阻断正常细胞周期进展的机制； 3. 研究Survivin和Stathamin在肿瘤细胞中抑制CDK1的分子后果，已知这两种药物在纺锤体组装中发挥着关键作用； 4. 利用MDR+和MDR-肿瘤细胞系，对两种候选药物ON01500-DMG和ON013100-P进行安全性、生物利用度和疗效研究； 5.确定ON013100对造血细胞生长和分化的体外和体内作用，并确定13100是否可以用作人类白血病的清除剂。