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.
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