Affiliation: Novartis Pharma Inc.Department of Oncology, WKL-125.4.10, CH-4002 Basel, Switzerland.
The importance of Cdks in cell cycle regulation, their interaction with oncogenes and tumor suppressors, and their frequent deregulation in human tumors, has encouraged an active search for agents capable of perturbing the function of Cdks. In our laboratories, a variety of selective and potent low molecular weight inhibitors directed against the ATP binding sites of the Cdk1, Cdk2 have been developed. Extensive biological profiling of two distinct classes of Cdk inhibitors - the phenylamino pyrimidines (PAPs) and trisubstituted purines has revealed distinct differences in their cellular effects in normal cells compared to tumor cells. Due to their intact G1 / S checkpoints, normal cells are shown to be reversibly blocked by these Cdk inhibitors in either the G1 / S-phase or at the G2 / M boarder. In transformed cells these control points are either absent or defective and treatment with the compounds resulted in pronounced proliferation block at the G2 / M transition. Furthermore, there is strong evidence that this G2 / M arrest is less well tolerated by the cells and consequently, they undergo apoptotic cell death. Finally, these dual Cdk1 / Cdk2 inhibitors are also found to be significantly more active on proliferating cells compared to quiescent cells reflecting their specific activity. Despite these encouraging results demonstrating a distinct outcome after treatment with such dual Cdk inhibitors in normal compared to de-regulated tumor cells, it remains to be determined whether a comparable therapeutic window might be observed in vivo experiments. Furthermore the intracellular kinase selectivity of inhibitors which are putatively selective in vitro remains a complicating feature that is only recently begun to be addressed by affinity chromatography and phosphoproteomics techniques. Once efficacy can be demonstrated in animal models at well-tolerated doses, there will be strong evidence for the development of cell cycle antagonists for cancer therapy.