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

Abstract

<P>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. </P><P> Objective: Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence. </P><P> 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. </P><P> 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. </P><P> 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 ligandbinding 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.</P>

Inhibiting CDK6 Activity by Quercetin Is an Attractive Strategy for Cancer Therapy

“…Cancer cells frequently show a gain of proliferation, cell cycle aberrations, loss of genomic and chromosomal stabilities, and metabolic alterations. , More than 80% of the cellular pathways such as cell cycle progression, transcription, DNA repair, and metabolic events are regulated by protein kinases through phosphorylation/dephosphorylation. − Out of different protein kinases, overexpression of cyclin-dependent kinases (CDKs) (EC 2.7.11.22) is associated with the majority of cancer types, and thus, identification and establishment of CDKs targeted inhibitors become an attractive approach for cancer therapy. − …”

Higher Accuracy Achieved for Protein–Ligand Binding Pose Prediction by Elastic Network Model-Based Ensemble Docking

“…CDK2 is a Ser/Thr protein kinase that plays a crucial role in timely regulating cell cycle progression, and its dysregulation in human cancers usually contributes to uncontrolled tumor proliferation. , Therefore, CDK2 is regarded as a pivotal pharmacological target for developing anticancer therapies and is extensively investigated in recent docking and MD simulation studies. ,,, These studies on CDK2 have revealed significant conformational flexibilities of the ATP-binding pocket, a site located at the interface of two subdomains. Here, we apply the iterANM method, which has been reported to explore the conformational space of domain movements efficiently, to generate the ensemble of apo CDK2 and evaluate its role in improving the prediction accuracy of molecular docking.…”

Multiparameter Kinetic Analysis for Covalent Fragment Optimization by Using Quantitative Irreversible Tethering (qIT)

“…This electrophile‐sensitive (ES) strategy has previously been successfully applied to c‐Src, Aurora A and EphB1 kinases by using established adenosine mimetics as starting scaffolds [21,22] . Here, we looked to apply the ES strategy to study cyclin‐dependent kinase 2 (Cdk2), which is a clinically important serine/threonine kinase in oncology, its activity is important for driving cell replication and is dependent upon association with a cyclin protein [23] . The high degree of active‐site homology within the Cdk family, has meant that developing Cdk2‐specific inhibitors has proved elusive and, as such, selective inhibitors of electrophile sensitive Cdk2 would be highly valuable tools [24] …”

“…[21,22] Here, we looked to apply the ES strategy to study cyclin-dependent kinase 2 (Cdk2), which is a clinically important serine/threonine kinase in oncology, its activity is important for driving cell replication and is dependent upon association with a cyclin protein. [23] The high degree of active-site homology within the Cdk family, has meant that developing Cdk2-specific inhibitors has proved elusive and, as such, selective inhibitors of electrophile sensitive Cdk2 would be highly valuable tools. [24] To generate an ES Cdk2 construct (Cdk2(ES)), we mutated the gatekeeper phenylalanine residue to cysteine (F80 C) to enable covalent binding in the active site.…”