New & more selective CDK inhibitors for improved cancer cell

A novel approach in the therapy of human malignancies based on the inhibition of cyclin dependent kinases (CDKs) has some limitations resulting from the targeting of multiple cellular pathways by distinct pharmacological CDK inhibitors. Interestingly, some CDKIs additionally affect the stability and activity of the tumour suppressor protein p53, thereby enhancing their anti-proliferative action towards cancer cells. Considering the fact that in about 50% of human cancers p53 protein is mutated or inactivated, the efficacy of the therapy of cancer cells by CDKIs would depend on their p53 status. Some cancer cells can proliferate despite CDK2 inhibition. However, the p53 activation mediated by CDK inhibitors could be essential for the efficacy of the CDKIs in the therapy of CDK2-independent cancers. Recently, involvement of the p53 pathway in the therapeutic action of roscovitine (ROSC), a very potent CDK inhibitor, was evidence by our group. Roscovitine arrested human breast cancer MCF-7 cells in the G2 phase of the cell cycle and concomitantly induced apoptosis. MCF-7 cells, lacking caspase-3 are generally resistant to other pro-apoptotic stimuli. We identified the mechanism by which Roscovitine initiates and supports the execution of apoptosis. Roscovitine activated and stabilized wt p53 protein via induction of its specific phosphorylation at serine 46. P-Ser46-p53 protein transcriptionally activated its downstream target, p53AIP1 protein that after de novo synthesis resulted in release of mitochondrial proteins and finally, induction of the apoptotic cascade. Our more recent results show that Roscovitine activates specific kinases localized in unique subcellular compartment. The above observations bring the rationale to dissect the different features of the purine/pyrimidine based CDK inhibitors such as 1. cell cycle arrest (CDK2 inhibitory action) 2. block of global transcription (CDK7/9 inhibitory action) and 3. wt p53 activation. Therefore, we decided to generate and to characterize the action of a panel of new purine/pyrimidine based CDK inhibitors by biochemical and cell-based systems. Our aim is to develop inhibitors exhibiting increased selectivity towards one of the three known cellular pathways and thereby get the tools for optimised treatments of distinct malignant entities. In the case of success, it would be of great interest to extend the experimental part based on the established tumour cell lines and to additionally include human primary cancer cells. Human leukaemia cells represent optimal model for the ex vivo experiments.

A novel approach in the therapy of human malignancies based on the inhibition of cyclin dependent kinases (CDKs) has some limitations resulting from the targeting of multiple cellular pathways by distinct pharmacological CDK inhibitors. Interestingly, some CDKIs additionally affect the stability and activity of the tumour suppressor protein p53, thereby enhancing their anti-proliferative action towards cancer cells. Considering the fact that in about 50% of human cancers p53 protein is mutated or inactivated, the efficacy of the therapy of cancer cells by CDKIs would depend on their p53 status. Some cancer cells can proliferate despite CDK2 inhibition. However, the p53 activation mediated by CDK inhibitors could be essential for the efficacy of the CDKIs in the therapy of CDK2-independent cancers. Recently, involvement of the p53 pathway in the therapeutic action of roscovitine (ROSC), a very potent CDK inhibitor, was evidence by our group. Roscovitine arrested human breast cancer MCF-7 cells in the G2 phase of the cell cycle and concomitantly induced apoptosis. MCF-7 cells, lacking caspase-3 are generally resistant to other pro-apoptotic stimuli. We identified the mechanism by which Roscovitine initiates and supports the execution of apoptosis. Roscovitine activated and stabilized wt p53 protein via induction of its specific phosphorylation at serine 46. P-Ser46-p53 protein transcriptionally activated its downstream target, p53AIP1 protein that after de novo synthesis resulted in release of mitochondrial proteins and finally, induction of the apoptotic cascade. Our more recent results show that Roscovitine activates specific kinases localized in unique subcellular compartment. The above observations bring the rationale to dissect the different features of the purine/pyrimidine based CDK inhibitors such as 1. cell cycle arrest (CDK2 inhibitory action) 2. block of global transcription (CDK7/9 inhibitory action) and 3. wt p53 activation. Therefore, we decided to generate and to characterize the action of a panel of new purine/pyrimidine based CDK inhibitors by biochemical and cell-based systems. Our aim is to develop inhibitors exhibiting increased selectivity towards one of the three known cellular pathways and thereby get the tools for optimised treatments of distinct malignant entities. In the case of success, it would be of great interest to extend the experimental part based on the established tumour cell lines and to additionally include human primary cancer cells. Human leukaemia cells represent optimal model for the ex vivo experiments.