Cyclin-Dependent Kinase 2 in Cellular Senescence and Cancer. A Structural and Functional Review

Background: Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies. Objective: Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence. Methods: There are over four hundreds of crystallographic structures available for CDK2, many of them with binding affinity information. We use this abundance of data to analyze the essential features responsible for the inhibition of CDK2 and its function in cancer and senescence. Results: The structural and affinity data available CDK2 makes it possible to have a clear view of the vital CDK2 residues involved in molecular recognition. A detailed description of the structural basis for ligand binding is of pivotal importance in the design of CDK2 inhibitors. Our analysis shows the relevance of the residues Leu 83 and Asp 86 for binding affinity. The recent findings revealing the participation of CDK2 inhibition in senescence open the possibility to explore the richness of structural and affinity data for a new era in the development of CDK2 inhibitors, targeting cellular senescence. Conclusion: Here, we analyzed structural information for CDK2 in combination with inhibitors and mapped the molecular aspects behind the strongest CDK2 inhibitors for which structures and ligand-binding affinity data were available. From this analysis, we identified the significant intermolecular interactions responsible for binding affinity. This knowledge may guide the future development of CDK2 inhibitors targeting cancer and cellular senescence.