Targeting Cell Cycle Machinery For Cancer Therapy

描述（由申请人提供）：细胞周期进程由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控途径的遗传改变有关，从而导致促进细胞周期进展的检查点的丢失。大多数正常细胞与肿瘤细胞在G1检查点控制方面存在差异，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途径。在这个应用程序中，我们提供的数据显示了一组新的小分子激酶抑制剂的衍生，这些抑制剂在细胞周期的G1期诱导正常细胞的生长停滞，同时诱导肿瘤细胞的有丝分裂停滞。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。随后的结果似乎是选择性杀死肿瘤细胞群，对正常细胞活力几乎没有影响。我们建议进行实验，旨在描述它们的作用机制及其作为癌症治疗药物的价值。目标是：1。测定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程的机制；3. 研究肿瘤细胞中CDK1抑制对Survivin和Stathamin（已知在纺锤体组装中起关键作用）的分子影响；4. 利用MDR+和MDR-肿瘤细胞系，开展ON01500- DMG和ON013100-P两种候选药物的安全性、生物利用度和有效性研究；和5。研究ON013100对人造血细胞生长分化的体内外影响，确定ON013100是否可作为人白血病的清净剂。

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.