European Journal of Cancer
Volume 46, Issue 1 , Pages 33-40 , January 2010

Cdc7 kinase – A new target for drug development

  • Ronan Swords

      Affiliations

    • Cancer Therapy and Research Center,University of Texas Health Science Center, San Antonio, TX, USA
    • Corresponding Author InformationCorresponding author: Tel.: +1 2104644229; fax: +1 2104505860.
    • ,
  • Devalingam Mahalingam

      Affiliations

    • Cancer Therapy and Research Center,University of Texas Health Science Center, San Antonio, TX, USA
    • ,
  • Michael O’Dwyer

      Affiliations

    • University College Hospital Galway, Department of Hematology, Galway, Ireland
    • ,
  • Corrado Santocanale

      Affiliations

    • University College Hospital Galway, Department of Hematology, Galway, Ireland
    • ,
  • Kevin Kelly

      Affiliations

    • Cancer Therapy and Research Center,University of Texas Health Science Center, San Antonio, TX, USA
    • ,
  • Jennifer Carew

      Affiliations

    • Cancer Therapy and Research Center,University of Texas Health Science Center, San Antonio, TX, USA
    • ,
  • Francis Giles

      Affiliations

    • Cancer Therapy and Research Center,University of Texas Health Science Center, San Antonio, TX, USA

Received 29 April 2009 ,Revised 14 August 2009 ,Accepted 17 September 2009.

References 

  1. D’Andrea AD, Grompe M. The Fanconi anaemia/BRCA pathway. Nat Rev Cancer. 2003;3(1):23–34
  2. Michelson RJ, Weinert T. Closing the gaps among a web of DNA repair disorders. Bioessays. 2000;22(11):966–969
  3. Coleman TR, Carpenter PB, Dunphy WG. The Xenopus Cdc6 protein is essential for the initiation of a single round of DNA replication in cell-free extracts. Cell. 1996;87(1):53–63
  4. Donovan S, et al. Cdc6p-dependent loading of Mcm proteins onto pre-replicative chromatin in budding yeast. Proc Natl Acad Sci USA. 1997;94(11):5611–5616
  5. Tanaka T, Knapp D, Nasmyth K. Loading of an Mcm protein onto DNA replication origins is regulated by Cdc6p and CDKs. Cell. 1997;90(4):649–660
  6. Jiang W, et al. Mammalian Cdc7-Dbf4 protein kinase complex is essential for initiation of DNA replication. EMBO J. 1999;18(20):5703–5713
  7. Hartwell LH. Sequential function of gene products relative to DNA synthesis in the yeast cell cycle. J Mol Biol. 1976;104(4):803–817
  8. Masai H, Miyake T, Arai K. hsk1+, a Schizosaccharomyces pombe gene related to Saccharomyces cerevisiae CDC7, is required for chromosomal replication. EMBO J. 1995;14(13):3094–3104
  9. Bousset K, Diffley JF. The Cdc7 protein kinase is required for origin firing during S phase. Genes Dev. 1998;12(4):480–490
  10. Takahashi TS, et al. Cdc7-Drf1 kinase links chromosome cohesion to the initiation of DNA replication in Xenopus egg extracts. Genes Dev. 2008;22(14):1894–1905
  11. Bailis JM, et al. Hsk1-Dfp1 is required for heterochromatin-mediated cohesion at centromeres. Nat Cell Biol. 2003;5(12):1111–1116
  12. Bernard P, et al. Requirement of heterochromatin for cohesion at centromeres. Science. 2001;294(5551):2539–2542
  13. Nasmyth K. Disseminating the genome: joining, resolving, and separating sister chromatids during mitosis and meiosis. Annu Rev Genet. 2001;35:673–745
  14. Matos J, et al. Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I. Cell. 2008;135(4):662–678
  15. Sawa M, Masai H. Drug design with Cdc7 kinase: a potential novel cancer therapy target. Drug Design Develop Therapy 2008:255–64.
  16. Kim JM, et al. Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene. 2008;27(24):3475–3482
  17. Takeda T, et al. A fission yeast gene, him1(+)/dfp1(+), encoding a regulatory subunit for Hsk1 kinase, plays essential roles in S-phase initiation as well as in S-phase checkpoint control and recovery from DNA damage. Mol Cell Biol. 1999;19(8):5535–5547
  18. Costanzo V, et al. An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol Cell. 2003;11(1):203–213
  19. Dierov J, Dierova R, Carroll M. BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint. Cancer Cell. 2004;5(3):275–285
  20. Tenca P, et al. Cdc7 is an active kinase in human cancer cells undergoing replication stress. J Biol Chem. 2007;282(1):208–215
  21. Im JS, Lee JK. ATR-dependent activation of p38 MAP kinase is responsible for apoptotic cell death in cells depleted of Cdc7. J Biol Chem. 2008;283(37):25171–25177
  22. Kim JM, Yamada M, Masai H. Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development. Mutat Res. 2003;532(1–2):29–40
  23. Montagnoli A, et al. Cdc7 inhibition reveals a p53-dependent replication checkpoint that is defective in cancer cells. Cancer Res. 2004;64(19):7110–7116
  24. Yoshizawa-Sugata N, et al. A second human Dbf4/ASK-related protein, Drf1/ASKL1, is required for efficient progression of S and M phases. J Biol Chem. 2005;280(13):13062–13070
  25. Johnston LH, Thomas AP. The isolation of new DNA synthesis mutants in the yeast Saccharomyces cerevisiae. Mol Gen Genet. 1982;186(3):439–444
  26. Chapman JW, Johnston LH. The yeast gene, DBF4, essential for entry into S phase is cell cycle regulated. Exp Cell Res. 1989;180(2):419–428
  27. Wang TS. Eukaryotic DNA polymerases. Annu Rev Biochem. 1991;60:513–552
  28. Yamada M, et al. A 63-base pair DNA segment containing an Sp1 site but not a canonical E2F site can confer growth-dependent and E2F-mediated transcriptional stimulation of the human ASK gene encoding the regulatory subunit for human Cdc7-related kinase. J Biol Chem. 2002;277(31):27668–27681
  29. Kumagai H, et al. A novel growth- and cell cycle-regulated protein, ASK, activates human Cdc7-related kinase and is essential for G1/S transition in mammalian cells. Mol Cell Biol. 1999;19(7):5083–5095
  30. Sato N, et al. Cell cycle regulation of chromatin binding and nuclear localization of human Cdc7-ASK kinase complex. Genes Cell. 2003;8(5):451–463
  31. Masai H, Arai K. Dbf4 motifs: conserved motifs in activation subunits for Cdc7 kinases essential for S-phase. Biochem Biophys Res Commun. 2000;275(1):228–232
  32. Montagnoli A, et al. Drf1, a novel regulatory subunit for human Cdc7 kinase. EMBO J. 2002;21(12):3171–3181
  33. Kurita M, et al. Overexpression of CR/periphilin downregulates Cdc7 expression and induces S-phase arrest. Biochem Biophys Res Commun. 2004;324(2):554–561
  34. Thalheim LB, et al. Transcriptional regulation of the intra-S-phase regulator CDC7 in human myeloid leukemic cells: a new downstream target of the C-Myb protooncogene. ASH Annu Meeting Abstr. 2005;106(11):1354
  35. Grishina I, Lattes B. A novel Cdk2 interactor is phosphorylated by Cdc7 and associates with components of the replication complexes. Cell Cycle. 2005;4(8):1120–1126
  36. Kiess M, Gill RM, Hamel PA. Expression and activity of the retinoblastoma protein (pRB)-family proteins, p107 and p130, during L6 myoblast differentiation. Cell Growth Differ. 1995;6(10):1287–1298
  37. Paggi MG, et al. Retinoblastoma protein family in cell cycle and cancer: a review. J Cell Biochem. 1996;62(3):418–430
  38. Suzuki-Takahashi I, et al. The interactions of E2F with pRB and with p107 are regulated via the phosphorylation of pRB and p107 by a cyclin-dependent kinase. Oncogene. 1995;10(9):1691–1698
  39. Ohtani H, et al. Intercellular adhesion molecule-1 induction: a sensitive and quantitative marker for cardiac allograft rejection. J Am Coll Cardiol. 1995;26(3):793–799
  40. Cho WH, et al. CDC7 kinase phosphorylates serine residues adjacent to acidic amino acids in the minichromosome maintenance 2 protein. Proc Natl Acad Sci USA. 2006;103(31):11521–11526
  41. Montagnoli A et al. Identification of Mcm2 phosphorylation sites by S-phase-regulating kinases. J Biol Chem 2006;281(15):10281–90.
  42. Vanotti E et al. Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships. J Med Chem 2008;51(3):487–501.
  43. Montagnoli A, et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008;4(6):357–365
  44. Bonte D, et al. Cdc7-Dbf4 kinase overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation. Neoplasia. 2008;10(9):920–931
  45. Costanzo V, Gautier J. Single-strand DNA gaps trigger an ATR- and Cdc7-dependent checkpoint. Cell Cycle. 2003;2(1):17
  46. Heffernan TP, et al. Cdc7–Dbf4 and the human S checkpoint response to UVC. J Biol Chem. 2007;282(13):9458–9468
  47. Weinreich M, Stillman B. Cdc7p–Dbf4p kinase binds to chromatin during S phase and is regulated by both the APC and the RAD53 checkpoint pathway. EMBO J. 1999;18(19):5334–5346
  48. Manke IA, et al. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell. 2005;17(1):37–48
  49. Feng D, et al. Inhibiting the expression of DNA replication-initiation proteins induces apoptosis in human cancer cells. Cancer Res. 2003;63(21):7356–7364
  50. Shreeram S, et al. Cell type-specific responses of human cells to inhibition of replication licensing. Oncogene. 2002;21(43):6624–6632
  51. Giaever G, et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature. 2002;418(6896):387–391
  52. Eissenberg JC, et al. Cdk9 is an essential kinase in Drosophila that is required for heat shock gene expression, histone methylation and elongation factor recruitment. Mol Genet Genom. 2007;277(2):101–114
  53. Salerno D, et al. Direct inhibition of CDK9 blocks HIV-1 replication without preventing T-cell activation in primary human peripheral blood lymphocytes. Gene. 2007;405(1–2):65–78
  54. Cai D, Byth KF, Shapiro GI. AZ703, an imidazo[1,2-a]pyridine inhibitor of cyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion of cyclin-dependent kinase 9. Cancer Res. 2006;66(1):435–444
  55. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770–1783
  56. Benakanakere I, et al. Natural and synthetic progestins accelerate 7,12-dimethylbenz[a]anthracene-initiated mammary tumors and increase angiogenesis in Sprague-Dawley rats. Clin Cancer Res. 2006;12(13):4062–4071
  57. Suggitt M, Bibby MC. 50 Years of preclinical anticancer drug screening: empirical to target-driven approaches. Clin Cancer Res. 2005;11(3):971–981
  58. Tonani EA. Heterobicyclic pyrazole derivatives as a kinase inhibitors. Patent: WO2004/007504; 2004.
  59. Lin EA. Substituted thiophene derivatives as anti-cancer agents. Patent: WO2005/095386; 2005.
  60. Leroy EA. New imadazolone derivatives, preparation thereof as drugs, pharmaceutical compositions, and use thereof as protein kinase inhibitors, in particular Cdc7. Patent: WO2008/046982; 2008.
  61. Shafer CM, et al. 4-(1H-indazol-5-yl)-6-phenylpyrimidin-2(1H)-one analogs as potent CDC7 inhibitors. Bioorg Med Chem Lett. 2008;18(16):4482–4485
  62. Bartek J, Lukas J, Bartkova J. Perspective: defects in cell cycle control and cancer. J Pathol. 1999;187(1):95–99
  63. Dixon H, Norbury CJ. Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function. Cell Cycle. 2002;1(6):362–368
  64. Nambiar S, et al. Identification and functional characterization of ASK/Dbf4, a novel cell survival gene in cutaneous melanoma with prognostic relevance. Carcinogenesis. 2007;28(12):2501–2510
  65. Burger M, et al. Mcm2 predicts recurrence hazard in stage Ta/T1 bladder cancer more accurately than CK20, Ki67 and histological grade. Brit J Cancer. 2007;96(11):1711–1715
  66. Gonzalez MA, et al. Minichromosome maintenance protein 2 is a strong independent prognostic marker in breast cancer. J Clin Oncol. 2003;21(23):4306–4313
  67. Szelachowska J et al. Mcm-2 protein expression predicts prognosis better than Ki-67 antigen in oral cavity squamocellular carcinoma. Anticancer Res 2006;26(3B):2473–8.
  68. Tokuyasu N, et al. Minichromosome maintenance 2 (MCM2) immunoreactivity in stage III human gastric carcinoma: clinicopathological significance. Gastric Cancer. 2008;11(1):37–46
  69. Yang J, et al. Prognostic significance of MCM2, Ki-67, gelsolin in non-small cell lung cancer. BMC Cancer. 2006;6:203
  70. Obermann EC, et al. Expression of minichromosome maintenance protein 2 as a marker for proliferation, prognosis in diffuse large B-cell lymphoma: a tissue microarray, clinico-pathological analysis. BMC Cancer. 2005;5:162
  71. Wei Q, et al. Genes differentially expressed in responsive and refractory acute leukemia. Front Biosci. 2006;11:977–982
  72. Sawa M, Hisao M. Drug design with Cdc7 kinase: a potential novel cancer therapy target. Drug Design Develop Therapy. 2008;2:255–264
  73. Montagnoli et al. A new and potent orally available class of Cdc7 inhibitors with anti-tumor activity. Poster presentation, 20th EORTC-NCI-AACR symposium on “Molecular targets and Cancer Therapeutics” Geneva 2008.

PII: S0959-8049(09)00717-5

doi: 10.1016/j.ejca.2009.09.020

European Journal of Cancer
Volume 46, Issue 1 , Pages 33-40 , January 2010

Article Tools

* Image Usage & Resolution