Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cell cycle kinases as therapeutic targets for cancer

Nature Reviews Drug Discovery volume 8, pages 547–566 (2009)Cite this article

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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

References

  1. Boye, E. & Grallert, B. The 2001 Nobel Prize in Physiology or Medicine. Tidsskr. Nor. Laegeforen. 121, 3500 (2001).

    CAS  PubMed  Google Scholar 

  2. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    CAS  PubMed  Google Scholar 

  3. Giacinti, C. & Giordano, A. RB and cell cycle progression. Oncogene 25, 5220–5227 (2006).

    CAS  PubMed  Google Scholar 

  4. Santamaria, D. et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448, 811–815 (2007). This study showed that genetic ablation of the mitotic kinase CDK1, but not the interphase kinases CDK2, CDK4 and CDK6, causes cell cycle arrest and is lethal to mouse embryos.

    CAS  PubMed  Google Scholar 

  5. Barr, A. R. & Gergely, F. Aurora-A: the maker and breaker of spindle poles. J. Cell Sci. 120, 2987–2996 (2007).

    CAS  PubMed  Google Scholar 

  6. Archambault, V. & Glover, D. M. Polo-like kinases: conservation and divergence in their functions and regulation. Nature Rev. Mol. Cell Biol. 10, 265–275 (2009).

    CAS  Google Scholar 

  7. Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Rev. Cancer 9, 153–166 (2009).

    CAS  Google Scholar 

  8. Kops, G. J. P. L., Weaver, B. A. A. & Cleveland, D. W. On the road to cancer: aneuploidy and the mitotic checkpoint. Nature Rev. Cancer. 5, 773 (2005). An excellent Review illustrating the relationship between chromosomal instability and cancer, and the strategy of complete inhibition of the mitotic checkpoint to kill cancer cells.

    CAS  Google Scholar 

  9. Kops, G. J. P. L., Foltz, D. R. & Cleveland, D. W. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc. Natl Acad. Sci. USA 101, 8699–8704 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Weaver, B. A. A., Silk, A. D. & Cleveland, D. W. Low rates of aneuploidy promote tumorigenesis while high rates of aneuploidy cause cell death and tumor suppression. Cell. Oncol. 30, 453–453 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Strock, C. J. et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells. Cancer Res. 66, 7509–7515 (2006).

    CAS  PubMed  Google Scholar 

  12. Larochelle, S. et al. Requirements for Cdk7 in the assembly of Cdk1/Cyclin B and activation of Cdk2 revealed by chemical genetics in human cells. Mol. Cell 25, 839–850 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Romano, G. & Giordano, A. Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and human diseases. Cell Cycle 7, 3664–3668 (2008).

    CAS  PubMed  Google Scholar 

  14. Shapiro, G. I. Cyclin-dependent kinase pathways as targets for cancer treatment. J. Clin. Oncol. 24, 1770–1783 (2006).

    CAS  PubMed  Google Scholar 

  15. Byrd, J. C. et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109, 399–404 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. George, S. et al. Phase I study of flavopiridol in combination with paclitaxel and carboplatin in patients with non-small-cell lung cancer. Clin. Lung Cancer 9, 160–165 (2008).

    CAS  PubMed  Google Scholar 

  17. Kodym, E. et al. The small-molecule CDK inhibitor, SNS-032, enhances cellular radiosensitivity in quiescent and hypoxic non-small cell lung cancer cells. Lung Cancer 1 Feb 2009 (doi:10.1016/j.lungcan.2008.12.026).

    PubMed  Google Scholar 

  18. Choong, I. C. et al. A diaminocyclohexyl analog of SNS-032 with improved permeability and bioavailability properties. Bioorg. Med. Chem. Lett. 18, 5763–5765 (2008).

    CAS  PubMed  Google Scholar 

  19. Fan, J. et al. Modifications of the isonipecotic acid fragment of SNS-032: analogs with improved permeability and lower efflux ratio. Bioorg. Med. Chem. Lett. 18, 6236–6239 (2008).

    CAS  PubMed  Google Scholar 

  20. Joshi, K. S. et al. In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol. Cancer Ther. 6, 918–925 (2007).

    CAS  PubMed  Google Scholar 

  21. Joshi, K. S. et al. P276-00, a novel cyclin-dependent inhibitor induces G1–G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol. Cancer Ther. 6, 926–934 (2007).

    CAS  PubMed  Google Scholar 

  22. Squires, M. S. et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol. Cancer Ther. 8, 324–332 (2009).

    CAS  PubMed  Google Scholar 

  23. DePinto, W. et al. In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials. Mol. Cancer Ther. 5, 2644–2658 (2006).

    CAS  PubMed  Google Scholar 

  24. Diab, S. et al. A phase I study of R547, a novel, selective inhibitor of cell cycle and transcriptional cyclin dependent kinases (CDKs). J. Clin. Oncol. 25, 3528 (2007).

    Google Scholar 

  25. Siemeister, G. et al. Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709. Biomed. Pharmacother. 60, 269–272 (2006).

    CAS  PubMed  Google Scholar 

  26. Scholz, A. et al. The oral multitarget tumour growth inhibitor, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model. Gut 58, 261–270 (2009).

    CAS  PubMed  Google Scholar 

  27. McClue, S. J. et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int. J. Cancer 102, 463–468 (2002).

    CAS  PubMed  Google Scholar 

  28. Villerbu, N., Gaben, A. M., Redeuilh, G. & Mester, J. Cellular effects of purvalanol A: a specific inhibitor of cyclin-dependent kinase activities. Int. J. Cancer 97, 761–769 (2002).

    CAS  PubMed  Google Scholar 

  29. Pennati, M. et al. Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: A possible role for survivin down-regulation. Mol. Cancer Ther. 4, 1328–1337 (2005).

    CAS  PubMed  Google Scholar 

  30. Bettayeb, K. et al. N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine. Mol. Cancer Ther. 7, 2713–2724 (2008).

    CAS  PubMed  Google Scholar 

  31. Bettayeb, K. et al. CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene 27, 5797–5807 (2008).

    CAS  PubMed  Google Scholar 

  32. Popowycz, F. et al. Pyrazolo[1,5-a]-1,3 5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue. J. Med. Chem. 52, 655–663 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Payton, M. et al. Discovery and evaluation of dual CDK1 and CDK2 inhibitors. Cancer Res. 66, 4299–4308 (2006).

    CAS  PubMed  Google Scholar 

  34. Emanuel, S. et al. The in vitro and in vivo effects of jnj-7706621: a dual inhibitor of cyclin-dependent kinases and Aurora kinases. Cancer Res. 65, 9038–9046 (2005).

    CAS  PubMed  Google Scholar 

  35. Seamon, J. A. et al. Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor. Mol. Cancer Ther. 5, 2459–2467 (2006).

    CAS  PubMed  Google Scholar 

  36. Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).

    CAS  PubMed  Google Scholar 

  37. Reddy, H. K. D. L. et al. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res. 65, 10174–10178 (2005).

    CAS  PubMed  Google Scholar 

  38. Landis, M. W., Pawlyk, B. S., Li, T., Sicinski, P. & Hinds, P. W. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9, 13–22 (2006).

    CAS  PubMed  Google Scholar 

  39. Yu, Q. et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23–32 (2006). References 36–39 showed that cyclin D1-dependent CDK4 activity is required for the development of Erbb2 - and Hras - induced breast cancer in mice, suggesting possible therapeutic uses of CDK4 inhibitors in patients with HER2-positive breast cancer.

    CAS  PubMed  Google Scholar 

  40. Rodriguez-Puebla, M. L. et al. Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation. Am. J. Pathol. 161, 405–411 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Miliani de Marval, P. L. et al. Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues. Mol. Cell. Biol. 24, 7538–7547 (2004).

    PubMed  PubMed Central  Google Scholar 

  42. Hu, M. et al. A requirement for cyclin-dependent kinase 6 in thymocyte development and tumorigenesis. Cancer Res. 69, 810–818 (2009). This work showed that CDK6-deficient mice are resistant to AKT-induced lymphomagenesis, supporting possible therapeutic uses of CDK6 inhibitors against human lymphoid tumours.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Toogood, P. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem. 48, 2388–2406 (2005).

    CAS  PubMed  Google Scholar 

  44. Goga, A., Yang, D., Tward, A. D., Morgan, D. O. & Bishop, J. M. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nature Med. 13, 820–827 (2007). This preliminary study showed that CDK1 inhibition might be a suitable therapeutic target in cells transformed by Myc but not other oncogenes.

    CAS  PubMed  Google Scholar 

  45. Vassilev, L. T. et al. Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1. Proc. Natl Acad. Sci. USA 103, 10660–10665 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ortega, S. et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nature Genet. 35, 25–31 (2003).

    CAS  PubMed  Google Scholar 

  47. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L. & Kaldis, P. Cdk2 knockout mice are viable. Curr. Biol. 13, 1775–1785 (2003). The work reported in references 46 and 47 showed that Cdk2 is not an essential gene for the mitotic cell cycle in mice.

    CAS  PubMed  Google Scholar 

  48. Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493–504 (2004).

    CAS  PubMed  Google Scholar 

  49. Rane, S. G. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nature Genet. 22, 44–52 (1999).

    CAS  PubMed  Google Scholar 

  50. Tsutsui, T. et al. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27Kip1 activity. Mol. Cell. Biol. 19, 7011–7019 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Martin, J. et al. Genetic rescue of Cdk4 null mice restores pancreatic β-cell proliferation but not homeostatic cell number. Oncogene 22, 5261–5269 (2003).

    CAS  PubMed  Google Scholar 

  52. Jirawatnotai, S. et al. Cdk4 is indispensable for postnatal proliferation of the anterior pituitary. J. Biol. Chem. 279, 51100–51106 (2004).

    CAS  PubMed  Google Scholar 

  53. Li, T., Inoue, A., Lahti, J. M. & Kidd, V. J. Failure to proliferate and mitotic arrest of CDK11 (p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development. Mol. Cell. Biol. 24, 3188–3197 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Barrière, C. et al. Mice thrive without Cdk4 and Cdk2. Mol. Oncol. 1, 72–83 (2007). This article provided genetic evidence that both CDK2 and CDK4 are dispensable for homeostasis in adult mice.

    PubMed  PubMed Central  Google Scholar 

  55. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    CAS  Google Scholar 

  56. Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).

    CAS  PubMed  Google Scholar 

  57. Rainey, M. D., Charlton, M. E., Stanton, R. V. & Kastan, M. B. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res. 68, 7466–7474 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Busby, E. C., Leistritz, D. F., Abraham, R. T., Karnitz, L. M. & Sarkaria, J. N. The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res. 60, 2108–2112 (2000).

    CAS  PubMed  Google Scholar 

  59. Matthews, D. J. et al. Pharmacological abrogation of S-phase checkpoint enhances the anti-tumor activity of gemcitabine in vivo. Cell Cycle 6, 104–110 (2007).

    CAS  PubMed  Google Scholar 

  60. Zabludoff, S. D. et al. AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies. Mol. Cancer Ther. 7, 2955–2966 (2008).

    CAS  PubMed  Google Scholar 

  61. Ashwell, S., Janetka, J. W. & Zabludoff, S. Keeping checkpoint kinases in line: new selective inhibitors in clinical trials. Expert Opin. Investig. Drugs 17, 1331–1340 (2008).

    CAS  PubMed  Google Scholar 

  62. Morgan, M. A. et al. Role of checkpoint kinase 1 in preventing premature mitosis in response to gemcitabine. Cancer Res. 65, 6835–6842 (2005).

    CAS  PubMed  Google Scholar 

  63. Xiao, Z., Xue, J., Sowin, T. J. & Zhang, H. Differential roles of checkpoint kinase 1, checkpoint kinase 2, and mitogen-activated protein kinase-2 in mediating DNA damage-induced cell cycle arrest: implications for cancer therapy. Mol. Cancer Ther. 5, 1935–1943 (2006).

    CAS  PubMed  Google Scholar 

  64. Carlessi, L. et al. Biochemical and cellular characterization of VRX0466617, a novel and selective inhibitor for the checkpoint kinase Chk2. Mol. Cancer Ther. 6, 935–944 (2007).

    CAS  PubMed  Google Scholar 

  65. Jobson, A. G. et al. Identification of a bis-guanylhydrazone [4, 4′-diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a novel chemotype for inhibition of Chk2 kinase. Mol. Pharmacol. 72, 876–884 (2007).

    CAS  PubMed  Google Scholar 

  66. Takai, H. et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21, 5195–5205 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Bartek, J. & Lukas, J. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3, 421–429 (2003).

    CAS  PubMed  Google Scholar 

  68. Xiao, Z. et al. Cyclin B1 is an efficacy-predicting biomarker for Chk1 inhibitors. Biomarkers 13, 579–596 (2008).

    CAS  PubMed  Google Scholar 

  69. Jordan, M. A. & Wilson, L. Microtubules as a target for anticancer drugs. Nature Rev. Cancer 4, 253–265 (2004).

    CAS  Google Scholar 

  70. Taylor, S. & Peters, J.-M. Polo and Aurora kinases: lessons derived from chemical biology. Curr. Opin. Cell Biol. 20, 77–84 (2008). This article reviews the use of small-molecule kinase inhibitors to elucidate the functions of specific mitotic kinases.

    CAS  PubMed  Google Scholar 

  71. Smith, M. A. et al. Pediatric preclinical testing program (PPTP) stage 2 testing of the Aurora A kinase inhibitor MLN8237. 20th EORTC-NCI-AACR Symposium, 21–24 October 2008, Geneva, Switzerland.

    Google Scholar 

  72. Huck, J., Zhang, S., Hyer, M. L. & Manfredi, M. G. Anti-tumor activity of the aurora A inhibitor MLN8237 in diffuse large B-cell lymphoma preclinical models. 50th ASH annual meeting, 6–8 December, 2008, San Francisco, USA.

    Google Scholar 

  73. Gorgun, G. et al. A novel aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell cycle arrest in experimental multiple myeloma models. 50th ASH annual meeting, 6–8 December, 2008, San Francisco, USA.

    Google Scholar 

  74. Mortlock, A. A. et al. Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of Aurora B kinase. J. Med. Chem. 50, 2213–2224 (2007).

    CAS  PubMed  Google Scholar 

  75. Yang, J. et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 110, 2034–2040 (2007).

    CAS  PubMed  Google Scholar 

  76. Walsby, E., Walsh, V., Pepper, C., Burnett, A. & Mills, K. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts. Haematologica 93, 662–669 (2008).

    CAS  PubMed  Google Scholar 

  77. Tao, Y. et al. Enhancement of radiation response in p53-deficient cancer cells by the aurora-B kinase inhibitor AZD1152. Oncogene 27, 3244–3255 (2008).

    CAS  PubMed  Google Scholar 

  78. Bray, M. R. ENMD-2076, an oral Aurora A and angiogenesis kinase inhibitor. AACR Annual Meeting, 12–16 April 2008, San Diego, USA.

  79. Gautschi, O. et al. Aurora kinases as anticancer drug targets. Clin. Cancer Res. 14, 1639–1648 (2008).

    CAS  PubMed  Google Scholar 

  80. Matthews, N., Visintin, C., Hartzoulakis, B., Jarvis, A. & Selwood, D. L. Aurora A and B kinases as targets for cancer: will they be selective for tumors? Expert Rev. Anticancer Ther. 6, 109–120 (2006).

    CAS  PubMed  Google Scholar 

  81. Girdler, F. et al. Molecular basis of drug resistance in Aurora kinases. Chem. Biol. 15, 552 (2008). This work describes drug-resistant aurora B mutants. Such mutants could represent novel anticancer drug targets.

    CAS  PubMed  Google Scholar 

  82. Dorer, R. K. et al. A small-molecule inhibitor of Mps1 blocks the spindle-checkpoint response to a lack of tension on mitotic chromosomes. Curr. Biol. 15, 1070–1076 (2005).

    CAS  PubMed  Google Scholar 

  83. Schmidt, M., Budirahardja, Y., Klompmaker, R. & Medema, R. H. Ablation of the spindle assembly checkpoint by a compound targeting Mps1. EMBO Reports 6, 866–872 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Scutt, P. J. et al. Discovery and exploitation of inhibitor-resistant Aurora and Polo kinase mutants for the analysis of mitotic networks. J. Biol. Chem. 284, 15880–15893 (2009). This work showed that the generation and characterization of drug-resistant aurora kinase mutants and polo-like kinase mutants is a powerful approach to validate small-molecule inhibitor-induced phenotypes against target and off-target effects.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Takai, N., Hamanaka, R., Yoshimatsu, J. & Miyakawa, I. Polo-like kinases (Plks) and cancer. Oncogene 24, 287–291 (2005).

    CAS  PubMed  Google Scholar 

  86. Simizu, S. & Osada, H. Mutations in the Plk gene lead to instability of Plk protein in human tumour cell lines. Nature Cell Biol. 2, 852–854 (2000).

    CAS  PubMed  Google Scholar 

  87. Guan, R. et al. Small interfering RNA-mediated Polo-like kinase 1 depletion preferentially reduces the survival of p53-defective, oncogenic transformed cells and inhibits tumor growth in animals. Cancer Res. 65, 2698–2704 (2005).

    CAS  PubMed  Google Scholar 

  88. Liu, X., Lei, M. & Erikson, R. L. Normal cells, but not cancer cells, survive severe Plk1 depletion. Mol. Cell. Biol. 26, 2093–2108 (2006).

    PubMed  PubMed Central  Google Scholar 

  89. Steegmaier, M. et al. BI 2536, a potent and selective inhibitor of Polo-like kinase 1, inhibits tumor growth in vivo. Curr. Biol. 17, 316–322 (2007).

    CAS  PubMed  Google Scholar 

  90. Lénárt, P. et al. The small-molecule inhibitor BI 2536 reveals novel insights into mitotic roles of Polo-like kinase 1. Curr. Biol. 17, 304–315 (2007).

    PubMed  Google Scholar 

  91. Mross, K. et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 26, 5511–5517 (2008).

    CAS  PubMed  Google Scholar 

  92. Santamaria, A. et al. Use of the novel Plk1 inhibitor zk-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis. Mol. Biol. Cell 18, 4024–4036 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Kothe, M. et al. Structure of the catalytic domain of human Polo-like kinase 1. Biochemistry (Mosc). 46, 5960–5971 (2007).

    CAS  Google Scholar 

  94. Claudio, P. P. et al. P130/pRb2 has growth suppressive properties similar to yet distinctive from those of retinoblastoma family members pRb and p107. Cancer Res. 54, 5556–5560 (1994).

    CAS  PubMed  Google Scholar 

  95. Claudio, P. P. et al. Functional analysis of pRb2/p130 interaction with cyclins. Cancer Res. 56, 2003–2008 (1996).

    CAS  PubMed  Google Scholar 

  96. Bagella, L. et al. A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo. Oncogene 26, 1829–1839 (2007). This study provides the first description of an RBL2-derived small peptide with antitumour activity in vivo.

    CAS  PubMed  Google Scholar 

  97. Brown, N. R. et al. The crystal structure of cyclin A. Structure 3, 1235–1247 (1995).

    CAS  PubMed  Google Scholar 

  98. Chen, Y.-N. P. et al. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc. Natl Acad. Sci. USA 96, 4325–4329 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Mendoza, N. et al. Selective cyclin-dependent kinase 2/cyclin A antagonists that differ from ATP site inhibitors block tumor growth. Cancer Res. 63, 1020–1024 (2003).

    CAS  PubMed  Google Scholar 

  100. Giordano, A., Bellacchio, E., Bagella, L. & Paggi, M. G. Interaction between the Cdk2/Cyclin A complex and a small molecule derived from the pRb2/p130 spacer domain: a theoretical model. Cell Cycle 6, 2591–2593 (2007).

    CAS  PubMed  Google Scholar 

  101. Wells, J. A. & McClendon, C. L. Reaching for high-hanging fruit in drug discovery at protein–protein interfaces. Nature 450, 1001–1009 (2007).

    CAS  PubMed  Google Scholar 

  102. Andrews, M. J. I. et al. Replace: a strategy for iterative design of cyclin-binding groove inhibitors. Chembiochem. 7, 1909–1915 (2006).

    CAS  PubMed  Google Scholar 

  103. Canela, N. et al. Identification of an hexapeptide that binds to a surface pocket in Cyclin A and inhibits the catalytic activity of the complex cyclin-dependent kinase 2–Cyclin A. J. Biol. Chem. 281, 35942–35953 (2006).

    CAS  PubMed  Google Scholar 

  104. Gold, M. G., Barford, D. & Komander, D. Lining the pockets of kinases and phosphatases. Curr. Opin. Struct. Biol. 16, 693–701 (2006).

    CAS  PubMed  Google Scholar 

  105. Anderson, K. et al. Binding of TPX2 to aurora A alters substrate and inhibitor interactions. Biochemistry (Mosc). 46, 10287–10295 (2007).

    CAS  Google Scholar 

  106. Jeyaprakash, A. A. et al. Structure of a survivin-borealin-INCENP core complex reveals how chromosomal passengers travel together. Cell 131, 271–285 (2007).

    CAS  PubMed  Google Scholar 

  107. Garcia-Alvarez, B., de Carcer, G., Ibanez, S., Bragado-Nilsson, E. & Montoyade, G. Molecular and structural basis of polo-like kinase 1 substrate recognition: implications in centrosomal localization. Proc. Natl Acad. Sci. USA 104, 3107–3112 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Reindl, W., Yuan, J., Krämer, A., Strebhardt, K. & Berg, T. Inhibition of Polo-like kinase 1 by blocking Polo-box domain-dependent protein–protein interactions. Chem. Biol. 15, 459–466 (2008).

    CAS  PubMed  Google Scholar 

  109. Whitehurst, A. W. et al. Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446, 815–819 (2007).

    CAS  PubMed  Google Scholar 

  110. Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nature Biotech. 26, 127–132 (2008).

    CAS  Google Scholar 

  111. Stiegler, P., Kasten, M. & Giordano, A. The RB family of cell cycle regulatory factors. J. Cell. Biochem. Suppl. 30–31, 30–36 (1998).

    PubMed  Google Scholar 

  112. Claudio, P. P., Tonini, T. & Giordano, A. The retinoblastoma family: twins or distant cousins? Genome Biology 3, 1–9 (2002).

    Google Scholar 

  113. Pajalunga, D. et al. Critical requirement for cell cycle inhibitors in sustaining nonproliferative states. J. Cell Biol. 176, 807–818 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Binne, U. K. et al. Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nature Cell Biol. 9, 225–232 (2007).

    CAS  PubMed  Google Scholar 

  115. Zhu, L., Harlow, E. & Dynlacht, B. D. P107 uses a p21cip1-related domain to bind cyclin/cdk2 and regulate interactions with E2F. Genes Dev. 9, 1740–1752 (1995).

    CAS  PubMed  Google Scholar 

  116. Woo, M. S., Sanchez, I. & Dynlacht, B. D. P130 and p107 use a conserved domain to inhibit cellular cyclin- dependent kinase activity. Mol. Cell. Biol. 17, 3566–3579 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Claudio, P. P. et al. Mutations in the retinoblastoma-related gene rb2/p130 in lung tumors and suppression of tumor growth in vivo by retrovirus-mediated gene transfer. Cancer Res. 60, 372–382 (2000).

    CAS  PubMed  Google Scholar 

  118. Howard, C. M. et al. Inducible pRb2/p130 expression and growth-suppressive mechanisms: evidence of a pRb2/p130, p27Kip1, and Cyclin E negative feedback regulatory loop. Cancer Res. 60, 2737–2744 (2000).

    CAS  PubMed  Google Scholar 

  119. De Luca, A. et al. A unique domain of pRb2/p130 acts as an inhibitor of Cdk2 kinase activity. J. Biol. Chem. 272, 20971–20974 (1997).

    CAS  PubMed  Google Scholar 

  120. Wikenheiser-Brokamp, K. Retinoblastoma family proteins: insights gained through genetic manipulation of mice. Cell. Mol. Life Sci. 63, 767–780 (2006).

    CAS  PubMed  Google Scholar 

  121. Dimaras, H. et al. Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum. Mol. Genet. 17, 1363–1372 (2008).

    CAS  PubMed  Google Scholar 

  122. Knudsen, E. S. & Knudsen, K. E. Tailoring to RB: tumour suppressor status and therapeutic response. Nature Rev. Cancer 8, 714–724 (2008).

    CAS  Google Scholar 

  123. Paggi, M. G. & Giordano, A. Who is the boss in the retinoblastoma family? The point of view of Rb2/p130, the little brother. Cancer Res. 61, 4651–4654 (2001).

    CAS  PubMed  Google Scholar 

  124. Ortega, S., Malumbres, M. & Barbacid, M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta 1602, 73–87 (2002).

    CAS  PubMed  Google Scholar 

  125. Perez de Castro, I., de Carcer, G. & Malumbres, M. A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis 28, 899–912 (2007).

    CAS  PubMed  Google Scholar 

  126. Yokoyama, H. et al. Cdk11 is a RanGTP-dependent microtubule stabilization factor that regulates spindle assembly rate. J. Cell Biol. 180, 867–875 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Hu, D., Valentine, M., Kidd, V. J. & Lahti, J. M. Cdk11p58 is required for the maintenance of sister chromatid cohesion. J. Cell Sci. 120, 2424–2434 (2007).

    CAS  PubMed  Google Scholar 

  128. Chandramouli, A. et al. Haploinsufficiency of the cdc2l gene contributes to skin cancer development in mice. Carcinogenesis 28, 2028–2035 (2007).

    CAS  PubMed  Google Scholar 

  129. Lavin, M. F. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nature Rev. Mol. Cell Biol. 9, 759–769 (2008).

    CAS  Google Scholar 

  130. Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 (2002).

    CAS  PubMed  Google Scholar 

  131. Vogel, C., Hager, C. & Bastians, H. Mechanisms of mitotic cell death induced by chemotherapy-mediated G2 checkpoint abrogation. Cancer Res. 67, 339–345 (2007).

    CAS  PubMed  Google Scholar 

  132. Ruchaud, S., Carmena, M. & Earnshaw, W. C. Chromosomal passengers: conducting cell division. Nature Rev. Mol. Cell Biol. 8, 798–812 (2007).

    CAS  Google Scholar 

  133. Yuen, K. W. & Desai, A. The wages of CIN. J. Cell Biol. 180, 661–663 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Zuo, L. et al. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet. 12, 97–99 (1996).

    CAS  PubMed  Google Scholar 

  135. Smalley, K. S. M. et al. Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression. Cancer Res. 68, 5743–5752 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Bogdanova, N. et al. A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer. Breast Cancer Res. Treat. 21 Sep 2008 (doi:10.1007/s10549-008-0189-9).

    PubMed  Google Scholar 

  137. Menoyo, A. et al. Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability. Cancer Res. 61, 7727–7730 (2001).

    CAS  PubMed  Google Scholar 

  138. Vassileva, V., Millar, A., Briollais, L., Chapman, W. & Bapat, B. Genes involved in DNA repair are mutational targets in endometrial cancers with microsatellite instability. Cancer Res. 62, 4095–4099 (2002).

    CAS  PubMed  Google Scholar 

  139. Wu, X., Dong, X., Liu, W. & Chen, J. Characterization of CHEK2 mutations in prostate cancer. Hum. Mutat. 27, 742–747 (2006).

    CAS  PubMed  Google Scholar 

  140. Matsuura, S. et al. Monoallelic BUB1B mutations and defective mitotic-spindle checkpoint in seven families with premature chromatid separation (PCS) syndrome. Am. J. Med. Genet. A 140, 358–367 (2006).

    PubMed  Google Scholar 

  141. Zhang, C. C. et al. AG-024322 is a potent and selective multi-targeted CDK inhibitor with broad spectrum anti-proliferative activity. Proc Amer. Assoc. Cancer Res. 46, Abstr. 4415 (2005).

  142. Zhang, C. C. et al. AG-024322 is a multi-targeted CDK inhibitor with potent antitumor activity in vivo. Proc Amer. Assoc. Cancer Res. 46, Abstr. 4413 (2005).

  143. Brown, A. et al. Toxicity and toxicokinetics of the cyclin-dependent kinase inhibitor AG-024322 in cynomolgus monkeys following intravenous infusion. Cancer Chemother. Pharmacol. 62, 1091–1101 (2008).

    CAS  PubMed  Google Scholar 

  144. Sedlacek, H. H. Mechanisms of action of flavopiridol. Crit. Rev. Oncol. Hematol. 38, 139–170 (2001).

    CAS  PubMed  Google Scholar 

  145. Christian, B. A., Grever, M. R., Byrd, J. C. & Lin, T. S. Flavopiridol in the treatment of chronic lymphocytic leukemia. Curr. Opin. Oncol. 19, 573–578 (2007).

    CAS  PubMed  Google Scholar 

  146. Owa, T. et al. Synthesis and biological evaluation of n-(7-indolyl)-3-pyridinesulfonamide derivatives as potent antitumor agents. Bioorg. Med. Chem. Lett. 12, 2097–100 (2002).

    CAS  PubMed  Google Scholar 

  147. Talbot, D. C. et al. A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer. Clin. Cancer Res. 13, 1816–22 (2007).

    CAS  PubMed  Google Scholar 

  148. Raje, N. et al. Preclinical activity of P276–00, a novel small-molecule cyclin-dependent kinase inhibitor in the therapy of multiple myeloma. Leukemia (2009).

  149. Fry, D. W. et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3, 1427–1438 (2004).

    CAS  PubMed  Google Scholar 

  150. Baughn, L. B. et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res. 66, 7661–7667 (2006).

    CAS  PubMed  Google Scholar 

  151. Menu, E. et al. A novel therapeutic combination using PD 0332991 and bortezomib: study in the 5T33MM myeloma model. Cancer Res. 68, 5519–5523 (2008).

    CAS  PubMed  Google Scholar 

  152. Benson, C. et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-roscovitine), administered twice daily for 7 days every 21 days. Br. J. Cancer 96, 29–37 (2006).

    PubMed  PubMed Central  Google Scholar 

  153. Shapiro, G. I. et al. A phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the novel cyclin-dependent kinase inhibitor SCH 727965 administered every 3 weeks in subjects with advanced malignancies. J. Clin. Oncol. 26, 3532 (2008).

    Google Scholar 

  154. Misra, R. N. et al. N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J. Med. Chem. 47, 1719–1728 (2004).

    CAS  PubMed  Google Scholar 

  155. Kamath, A. V., Chong, S., Chang, M. & Marathe, P. H. P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in rats. Cancer Chemother. Pharmacol. 55, 110–116 (2005).

    CAS  PubMed  Google Scholar 

  156. Smolewski, P. Terameprocol, a novel site-specific transcription inhibitor with anticancer activity. IDrugs 11, 204–214 (2008).

    CAS  PubMed  Google Scholar 

  157. Scott, E. et al. A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI™), in patients with advanced solid tumours. Cancer Chemother. Pharmacol. 12 Mar 2009 (doi:0.1007/s00280-009-0968-y).

  158. Seynaeve, C., Kazanietz, M., Blumberg, P., Sausville, E. & Worland, P. Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. Mol. Pharmacol. 45, 1207–1214 (1994).

    CAS  PubMed  Google Scholar 

  159. Wilkinson, R. W. et al. AZD1152, a selective inhibitor of aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin. Cancer Res. 13, 3682–3688 (2007).

    CAS  PubMed  Google Scholar 

  160. Howard, S. et al. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J. Med. Chem. 52, 379–388 (2009).

    CAS  PubMed  Google Scholar 

  161. Griffiths, G. et al. Anti-tumor activity of CYC116, a novel small molecule inhibitor of Aurora kinases and VEGFR2. AACR Annual Meeting, 12–16 April 2008, San Diego, USA.

    Google Scholar 

  162. Anderson, K. et al. Biochemical characterization of GSK1070916, a potent and selective inhibitor of aurora B and aurora C kinases with an extremely long residence time. Biochem. J. 420, 259–265 (2009).

    CAS  PubMed  Google Scholar 

  163. Carpinelli, P. et al. PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer. Mol Cancer Ther 6, 3158–3168 (2007).

    CAS  PubMed  Google Scholar 

  164. Fancelli, D. et al. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: Identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J. Med. Chem. 49, 7247–7251 (2006).

    CAS  PubMed  Google Scholar 

  165. Renshaw, J. S. et al. A phase I two arm trial of AS703569 (R763), an orally available aurora kinase inhibitor, in subjects with solid tumors: preliminary results. J. Clin. Oncol. (Meeting Abstracts) 25, 14130 (2007).

    Google Scholar 

  166. Evanchik, M. J. et al. Sns-314, a potent inhibitor of Aurora kinases, has preclinical anti-activity and induces apoptosis. AACR Annual Meeting, 12–16 April 2008, San Diego, USA.

    Google Scholar 

  167. Godl, K. et al. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling. Cancer Res. 65, 6919–6926 (2005).

    CAS  PubMed  Google Scholar 

  168. Laird, A. D. et al. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 60, 4152–4160 (2000).

    CAS  PubMed  Google Scholar 

  169. Shaheen, R. M. et al. Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Cancer Res. 61, 1464–1468 (2001).

    CAS  PubMed  Google Scholar 

  170. Carter, T. A. et al. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc. Natl Acad. Sci. USA 102, 11011–11016 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Lansing, T. J. et al. In vitro biological activity of a novel small-molecule inhibitor of polo-like kinase 1. Mol. Cancer Ther. 6, 450–459 (2007).

    CAS  PubMed  Google Scholar 

  172. Garland, L. L., Taylor, C., Pilkington, D. L., Cohen, J. L. & Von Hoff, D. D. A Phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with Polo-like kinase-1-interacting properties, in patients with advanced solid tumors. Clin. Cancer Res. 12, 5182–5189 (2006).

    CAS  PubMed  Google Scholar 

  173. Takagi, M. et al. In vivo antitumor activity of a novel sulfonamide, HMN-214, against human tumor xenografts in mice and the spectrum of cytotoxicity of its active metabolite, HMN-176. Invest. New Drugs 21, 387–399 (2003).

    CAS  PubMed  Google Scholar 

  174. Tanaka, H. et al. HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y. Cancer Res. 63, 6942–6947 (2003).

    CAS  PubMed  Google Scholar 

  175. Iizuka, D., Ogura, A., Kuwabara, M. & Inanami, O. Purvalanol A induces apoptosis and downregulation of antiapoptotic proteins through abrogation of phosphorylation of JAK2/STAT3 and RNA polymerase II. Anticancer Drugs 19, 565–572 (2008).

    CAS  PubMed  Google Scholar 

  176. Byth, K. F., Geh, C., Forder, C. L., Oakes, S. E. & Thomas, A. P. The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor. Mol. Cancer Ther. 5, 655–664 (2006).

    CAS  PubMed  Google Scholar 

  177. Cai, D., Byth, K. F. & Shapiro, G. I. AZ703, an imidazo[1,2-α]pyridine inhibitor of cyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion of cyclin-dependent kinase 9. Cancer Res. 66, 435–444 (2006).

    CAS  PubMed  Google Scholar 

  178. Lin, R. et al. 1-acyl-1h-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: Synthesis and evaluation of biological activities. J. Med. Chem. 48, 4208–4211 (2005).

    CAS  PubMed  Google Scholar 

  179. Wang, S., Ayyub, E. & Lamphere, L. Evaluation of selective biomarkers of the broad spectrum CDK inhibitor: RGB-286199. Proc. Amer. Assoc. Cancer Res. 46, Abstr. 4428 (2005).

  180. Oalmann, C. J. et al. Indenopyrazoles: potent, broad-spectrum cyclin dependent kinase inhibitors. 23 2ndACS National Meeting, 10–14 Sep 2006, San Francisco, USA.

  181. Ivanov, V., Zhou, H., Partridge, M. & Hei, T. Inhibition of ataxia telangiectasia mutated kinase activity enhances TRAIL-mediated apoptosis in human melanoma cells. Cancer Res. 69, 3510 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Sha, S.-K. et al. Cell cycle phenotype-based optimization of G2-abrogating peptides yields CBP501 with a unique mechanism of action at the G2 checkpoint. Mol. Cancer Ther. 6, 147–153 (2007).

    CAS  PubMed  Google Scholar 

  183. Sardon, T., Cottin, T., Xu, J., Giannis, A. & Vernos, I. Development and biological evaluation of a novel aurora A kinase inhibitor. Chembiochem. 10, 464–478 (2009).

    CAS  PubMed  Google Scholar 

  184. Akahane, D., Tauchi, T., Okabe, S., Nunoda, K. & Ohyashiki, K. Activity of a novel Aurora kinase inhibitor against the T315I mutant form of BCR-ABL: in vitro and in vivo studies. Cancer Sci. 99, 1251–1257 (2008).

    CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Oncology Research Centre of Mercogliano, Mercogliano, Avellino, Italy

    Silvia Lapenna

  2. Department of Human Pathology and Oncology, University of Siena, Siena, Italy

    Silvia Lapenna & Antonio Giordano

  3. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, USA

    Antonio Giordano

Authors
  1. Silvia Lapenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Silvia Lapenna or Antonio Giordano.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Related links

Related links

DATABASES

OMIM

ataxia-telangiectasia

FURTHER INFORMATION

The Human Health Foundation

The Sbarro Health Research Organization

SUPPLEMENTARY INFORMATION

See online article

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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2907

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing