Background The cell cycle is comprised of a series of highly coor

Background The cell cycle is comprised of a series of highly coordi nated events culminating in cell growth and protocol division. Cyclin dependent kinases and their cyclin coun terparts strictly regulate and drive cell cycle progression and different CDK/cyclin complexes are responsible for the timely occurrence of each phase transition in order to maintain genetic integrity throughout generations. Cancer cells have been frequently found to have a de regulated CDK activity allowing them to escape the nor mal cell cycle and proliferate uncontrollably. For these reasons CDKs have been considered attractive targets for cancer therapy and several CDK inhibitors have been developed and are under intense investigation.

R Roscovitine, one of the most promising members of the CDK inhibitor family, is an orally available adeno sine analogue prominently targeting CDK2 with a low off target effect on other members of the human kinome, and a nice toxicity profile. Inhibitors,Modulators,Libraries In preclinical studies Roscovitine has shown significant in vitro and in vivo antitumor activity on a wide panel of human cancers and is currently in phase II clinical trials. Since preclinical experimentation, it has become evident that, CDK inhibitors, such as Roscovitine, may actually curb the activity of DNA repair machinery, hence becoming an attractive candidate for therapeutic asso ciation with either radiation therapy or genotoxic Inhibitors,Modulators,Libraries agent based chemotherapy. However, the mechan ism of this inhibition is still elusive.

One of the proposed means for CDK inhibitors to affect DNA repair is through checkpoint deregulation, but increasing evidence supports a complex net work of direct interactions Inhibitors,Modulators,Libraries between individual CDKs and proteins that play a key role in DNA damage repair. It is known that different DNA repair pathways are preferentially activated at specific stages of the cell cycle possibly suggesting a functional crosstalk between CDK/cyclin complexes and DNA repair mechanisms. In particular, CDK2 has been shown to interact with p53, BRCA1, BRCA2, Ku70 and both, CDK1 and CDK2, can modulate BRCA1 BARD1 activity. Moreover, CDK2 knock down cells have an attenuated capacity to repair DNA damage suggest ing a pivotal role for CDK2 in DDR. Given the ability of CDKs to Inhibitors,Modulators,Libraries compensate for each other in Inhibitors,Modulators,Libraries vivo, overall CDK activity has been proposed to be influential in DDR regulation however CDK2 function seems to have a specific role in some survival pathways.

Cyclins, similarly to CDKs, have been correlated to DDR. Cyclin E levels are upregulated under genotoxic stress conditions and a post translational cleavage generates an 18 amino acid read more peptide, which has been shown to interact with Ku70 promoting the release of the pro apoptotic factor Bax from the inactivating complex Bax/Ku70. Moreover, an increasing amount of data suggests an important role in DDR for the A type cyclins, and in particular for cyclin A1.

Background The cell cycle is comprised of a series of highly coor