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Cell cycle kinases as therapeutic targets for cancer

Key Points

  • The activity of several protein kinases involved in the regulation of the cell cycle — including cyclin-dependent kinases (CDKs), DNA damage checkpoint and spindle assembly checkpoint regulators, aurora kinases and polo-like kinases — is often abnormal in cancer cells.

  • Over the past two decades, an intense search for drugs that inhibit cell cycle protein kinases has led to the identification of a plethora of small-molecule inhibitors, although no such inhibitors have yet been approved for commercial use.

  • Members of the CDK family of serine–threonine protein kinases have received particular attention owing to their crucial role in cell proliferation and their frequent upregulation in human cancer. Whereas first-generation CDK inhibitors have shown only minor efficacy in clinical trials, several second-generation compounds are considerably more potent and/or specific than the earlier inhibitors. Furthermore, recent genetic studies have provided valuable information for the validation of specific CDK variants as potential targets in cancer therapy.

  • The aurora kinases and polo-like kinases are important regulators of the centrosome cycle and spindle assembly. Chemical inhibition has emerged as a powerful approach to advance our understanding of these mitotic kinases, and numerous inhibitors are being developed as potential anticancer drugs.

  • Other cell cycle regulators, such as the DNA damage checkpoint kinases and spindle-assembly checkpoint proteins, are also being evaluated as potential new drug targets to improve cancer therapy.

  • This Review discusses the potential use of cell cycle protein kinases as therapeutic targets for cancer, and provides a comprehensive overview of the recent advances in this field. The structure and biological effects of cell cycle kinase inhibitors that have been publicly disclosed as being in clinical trials or advanced preclinical evaluation are reported. Novel strategies for the design of cell cycle inhibitors that target protein domains distinct from the ATP-binding pocket are also discussed.

Abstract

Several families of protein kinases orchestrate the complex events that drive the cell cycle, and their activity is frequently deregulated in hyperproliferative cancer cells. Although several molecules that inhibit cell cycle kinases have been developed and clinically screened as potential anticancer agents, none of these has been approved for commercial use and an effective strategy to specifically control malignant cell proliferation has yet to be established. However, recent genetic and biochemical studies have provided information about the requirement for certain cell cycle kinases by specific tumours and specialized tissue types. Here, we discuss the potential and limitations of established cell cycle kinases as targets in anticancer drug discovery as well as novel strategies for the design of new agents.

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Figure 1: Cell cycle regulation by protein kinases of potential interest in cancer therapy.
Figure 2: Selected chemical structures of kinase inhibitors.

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Acknowledgements

This work was supported by grants to A.G. from the National Institutes of Health; the Human Health Foundation, Spoleto-Terni, Italy (see Further information); and the Sbarro Health Research Organization, USA (see Further information).

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Supplementary information

Supplementary information S1 (table)

Selected inhibitors of cell cycle kinases in clinical trials* (PDF 1490 kb)

Supplementary information S2 (table)

Selected inhibitors of cell cycle kinases in preclinical screening (PDF 499 kb)

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ataxia-telangiectasia

FURTHER INFORMATION

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S1 (table)

S2 (table)

Glossary

Cyclins

A family of proteins that are involved in cell cycle progression. They are transiently expressed in response to growth signals in order to regulate the timely activation of cyclin-dependent kinases.

Cell cycle checkpoints

A series of surveillance pathways which ensure that cells pass accurate copies of their genome on to the next generation.

Centrosome

The main microtubule-organizing centre of the cell. It is formed by two centrioles, which are cylindrical structures made of bundles of microtubules.

Microtubule

A hollow tube made of polymers of α- and β-tubulin subunits.

Anaphase-promoting complex or cyclosome

A multi-subunit E3 ubiquitin ligase that targets key regulators of mitosis, such as cyclin B, aurora kinases and polo-like kinases, for destruction through direct polyubiquitylation.

Kinetochore

A multi-protein structure positioned at the central constriction of each mitotic chromosome (centromere) at which spindle microtubules attach. Unattached kinetochores are the signals for activation of the surveillance mechanism known as the spindle assembly checkpoint.

Spindle midzone

Organized bundles of antiparallel microtubules that form in late mitosis and are thought to be important for signalling the location of cleavage of the plasma membrane.

Anaphase

The process by which sister chromatids move to opposite spindle poles.

Pan-CDK inhibitor

A cyclin-dependent kinase (CDK) inhibitor with a broad specificity for CDKs.

Erbb2

The rodent orthologue of the human epidermal growth factor receptor 2 (HER2) gene. At least one-quarter of human breast cancers overexpress HER2, an event which often leads to increased cyclin D1 expression levels.

Mitotic catastrophe

A form of apoptosis that occurs during mitosis and may result from deficient cell cycle checkpoints, particularly the DNA damage checkpoint and the spindle assembly checkpoint.

Li–Fraumeni syndrome

A familial cancer syndrome that arises from a checkpoint kinase 2 (CHK2)-truncating mutation (1100delC). It is characterised by multiple tumours at a young age, particularly breast cancer and sarcoma.

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Lapenna, S., Giordano, A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 8, 547–566 (2009). https://doi.org/10.1038/nrd2907

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