Cyclin-Dependent Kinase-2 as a Target for Cancer Therapy: Progress in the Development of CDK2 Inhibitors as Anti-Cancer Agents

Abstract

Cyclin-dependent kinase-2 (CDK2) is a member of protein kinase family. It plays an important role in regulating various events of eukaryotic cell division cycle. Accumulated evidences indicated that over expression of CDK2 should cause the abnormal regulation of cell-cycle, which would be directly associated with hyperproliferation in cancer cells. Therefore, CDK2 was regarded as a potentially therapeutic target for cancer therapy. Knowledge of crystallography and availability of X-ray crystal structure of CDK2 have enabled us to understand the mode of CDK2 inhibition, which facilitated the development of numerous CDK2 inhibitors. Some of the CDK2 inhibitors were investigated clinically for their potential as anti-cancer agents. In this review, we present the structure, functions and activation of CDK2 by cyclin binding with special focus on recent advances in the development of different classes of CDK2 inhibitors. We also summarize different strategies to achieve subtype specificity either by targeting a binding pocket other than ATP, i.e. allosteric ligand binding site or by natural protein inhibitors capable to disrupt CDK2-cyclin complexes. It is possible to develop pharmacologically relevant cytotoxic agents by specifically inhibiting CDK2 activity with lesser toxicity than traditional chemotherapeutic agents.

Knockdown of SIRT1 Suppresses Bladder Cancer Cell Proliferation and Migration and Induces Cell Cycle Arrest and Antioxidant Response through FOXO3a-Mediated Pathways

“…Cyclin-dependent kinases (CDKs) are a family of protein kinases playing vital roles in regulating cell cycle [55]. Among them CDK4 and CDK6 are responsible for helping cells getting out from G0 phase and into G1 phase [56, 57]; meanwhile CDK2 plays its role in G1 phase [58]. Downregulation of CDK2/4/6 could lead to cell cycle arrest at G0/G1 phase [59], which may explain our result of flow cytometry analysis (Figure 2).…”

Cyclin dependent kinase (CDK) inhibitors as anticancer drugs

“…For additional information the reader is directed to review articles for comprehensive coverage of the CDK arena and references therein. 15,[24][25][26][27][28][29][30][31][32] CDKs are unique in the protein kinase family because their activity depends on the association with their partner cyclins, and this could be a potential advantage for inhibitor design. The recognition of CDK-cyclin complexes by different interacting proteins (tumor suppressors, transcription factors) occurs at least in part through protein-protein interaction (PPI).…”

Structural prediction of the interaction of the tumor suppressor p27KIP1 with cyclin A/CDK2 identifies a novel catalytically relevant determinant

“…Different cyclins are overexpressed while the expression of CDK inhibitors is reduced in different tumor entities [2]. These findings suggest that CDKs are promising targets for pharmaceutical interventions and CDK2 inhibitors are in clinical trials [3–5]. Moreover, Wee1, a tyrosine kinase repressor of CDK1 and CDK2, is targeted by small molecules to prevent repression of CDK1 and CDK2 in response to DNA damage and thus enhance genetic instability and apoptosis [6].…”