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Cyclin-Dependent Kinases and Their Small-Molecule Inhibitors in Cancer Therapy

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Targets for Cancer Chemotherapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Cell cycle, the process by which cells reproduce, plays a central role in the growth and development of all life (1–4). Deregulation of cell cycle control, leading to a net increase in the total number of cells, is one of the initial events in the development of all cancers (5). Most drugs that are used to treat cancer rely on this differential cell proliferation to achieve selective toxicity. Considerable progress has been made in understanding cell cycle progression in normal and neoplastic situations, the challenge is to translate this understanding into useful cancer therapies (6–18). In this chapter, we discuss the role of cyclin-dependent kinases (CDKs) in cell cycle transitions and how their activity is controlled in normal and cancerous states. We will discuss the modulation of CDK activity by small-molecule inhibitors, and how some of these drugs act in preclinical and clinical models of cancer.

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References

  1. Nurse P. A long twentieth century of the cell cycle and beyond. Cell 2000; 100: 71–78.

    PubMed  CAS  Google Scholar 

  2. Nurse P. The incredible life and times of biological cells. Science 2000; 289: 1711–1716.

    PubMed  CAS  Google Scholar 

  3. Ewen ME. Where the cell cycle and histones meet. Genes Dev 2000; 14: 2265–2270.

    PubMed  CAS  Google Scholar 

  4. Tannoch VJ, Hinds PW, Tsai LH. Cell cycle control. Adv Exp Med Biol 2000; 465: 127–140.

    PubMed  CAS  Google Scholar 

  5. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57–70.

    PubMed  CAS  Google Scholar 

  6. Sausville EA, Senderowicz AM. Chemical cyclin-dependent kinase inhibitors. In: Gutkind JS, ed. Signalling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases. Humana Press Inc., Totowa, NJ, 2000, pp. 557–567.

    Google Scholar 

  7. Sausville EA, Johnson J, Alley M, Zaharevitz D, Senderowicz AM. Inhibition of CDKs as a therapeutic modality. Ann NYAcad Sci 2000; 910:207–221; discussion 221–222.

    Google Scholar 

  8. Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 2000; 92: 376–387.

    PubMed  CAS  Google Scholar 

  9. Buolamwini JK. Cell cycle molecular targets in novel anticancer drug discovery. Curr Pharm Des 2000; 6: 379–392.

    PubMed  CAS  Google Scholar 

  10. Crews CM, Mohan R. Small-molecule inhibitors of the cell cycle. Curr Opin Chem Biol 2000; 4: 47–53.

    PubMed  CAS  Google Scholar 

  11. Damiens E. Molecular events that regulate cell proliferation: an approach for the development of new anticancer drugs. Prog Cell Cycle Res 2000; 4: 219–233.

    PubMed  CAS  Google Scholar 

  12. Garrett MD, Fattaey A. CDK inhibition and cancer therapy. Curr Opin Genet Dev 1999; 9: 104–111.

    PubMed  CAS  Google Scholar 

  13. McDonald ER III, El-Deiry WS. Cell cycle control as a basis for cancer drug development. Int J Oncol 2000; 16: 871–886.

    PubMed  CAS  Google Scholar 

  14. Rao RN. Targets for cancer therapy in the cell cycle pathway. Curr Opin Oncol 1996; 8: 516524.

    Google Scholar 

  15. Shapiro GI, Harper JW. Anticancer drug targets: cell cycle and checkpoint control. J Clin Invest 1999; 104: 1645–1653.

    PubMed  CAS  Google Scholar 

  16. Sielecki TM, Boylan JF, Benfield PA, Trainor GL. Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. J Med Chem 2000; 43: 1–18.

    PubMed  CAS  Google Scholar 

  17. Brooks G, La Thangue NB. The cell cycle and drug discovery: the promise and the hope. Drug Discov Today 1999; 4: 455–464.

    PubMed  CAS  Google Scholar 

  18. Kaelin WG Jr. Choosing anticancer drug targets in the postgenomic era. J Clin Invest 1999; 104: 1503–1506.

    PubMed  CAS  Google Scholar 

  19. Sherr O. Cancer cell cycles. Science 1996; 274: 1672–1677.

    PubMed  CAS  Google Scholar 

  20. Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 2000; 60: 3689–3695.

    PubMed  CAS  Google Scholar 

  21. Pardee AB. A restriction point for control of normal animal cell proliferation. Proc NatlAcad Sci USA 1974; 71: 1286–1290.

    CAS  Google Scholar 

  22. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science 1989; 246: 629–634.

    PubMed  CAS  Google Scholar 

  23. Elledge SJ. Cell cycle checkpoints: preventing an identity crisis. Science 1996; 274: 1664–1672.

    PubMed  CAS  Google Scholar 

  24. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of Gl-phase progression. Genes Dev 1999; 13: 1501–1512.

    PubMed  CAS  Google Scholar 

  25. van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 1993; 262: 2050–2054.

    PubMed  Google Scholar 

  26. Braun K, Holz]. G, Soucek T, Geisen C, Moroy T, Hengstschlager M. Investigation of the cell cycle regulation of cdk3-associated kinase activity and the role of cdk3 in proliferation and transformation. Oncogene 1998; 17: 2259–2269.

    PubMed  CAS  Google Scholar 

  27. Hofmann F, Livingston DM. Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during GI exit. Genes Dev 1996; 10: 851–861.

    PubMed  CAS  Google Scholar 

  28. Arooz T, Yam CH, Siu WY, Lau A, Li KK, Poon RY. On the concentrations of cyclins and cyclin-dependent kinases in extracts of cultured human cells. Biochemistry 2000; 39: 94949501.

    Google Scholar 

  29. Koepp DM, Harper JW, Elledge SJ. How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell 1999; 97: 431–434.

    PubMed  CAS  Google Scholar 

  30. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev 2000; 14: 2393–2409.

    PubMed  CAS  Google Scholar 

  31. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995; 81: 323–330.

    PubMed  CAS  Google Scholar 

  32. Dyson N. The regulation of E2F by pRB-family proteins. Genes Dey 1998; 12: 2245–2262.

    CAS  Google Scholar 

  33. Adams PD. Regulation of the retinoblastoma tumor suppressor protein by cyclin/cdks. Biochimica et Biophysica Acta 2001; 1471: M123 - M133.

    PubMed  CAS  Google Scholar 

  34. Brown VD, Phillips RA, Gallie BL. Cumulative effect of phosphorylation of pRB on regulation of E2F activity. Mol Cell Biol 1999; 19: 3246–3256.

    CAS  Google Scholar 

  35. Adams PD, Sellers WR, Sharma SK, Wu AD, Nalin CM, Kaelin WG. Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors. Mol Cell Biol 1996; 16: 6623–6633.

    PubMed  CAS  Google Scholar 

  36. Harbour JW, Luo RX, Dei Santi A, Postigo AA, Dean DC. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through GI. Cell 1999; 98: 859–869.

    PubMed  CAS  Google Scholar 

  37. Lundberg AS, Weinberg RA. Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes. Mol Cell Biol 1998; 18: 753–761.

    PubMed  CAS  Google Scholar 

  38. Montagnoli A, Fiore F, Eytan E, Carrano AC, Draetta GF, Hershko A, Pagano M. Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation. Genes Dey 1999; 13: 1181–1189.

    CAS  Google Scholar 

  39. Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE. Cyclin E-CDK2 is a regulator of p27Kipl. Genes Dey 1997; 11: 1464–1478.

    CAS  Google Scholar 

  40. Hoffmann I, Draetta G, Karsenti E. Activation of the phosphatase activity of human cdc25A by a cdk2-cyclin E dependent phosphorylation at the Gl/S transition. EMBO J 1994; 13: 4302–4310.

    CAS  Google Scholar 

  41. Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in cajal bodies promotes histone gene transcription. Genes Dey 2000; 14: 2298–2313.

    CAS  Google Scholar 

  42. Zhao J, Kennedy BK, Lawrence BD, Barbie DA, Matera AG, Fletcher JA, Harlow E. NPAT links cyclin E-Cdk2 to the regulation of replication-dependent histone gene transcription. Genes Dey 2000; 14: 2283–2297.

    CAS  Google Scholar 

  43. Laman H, Coverley D, Krude T, Laskey R, Jones N. Viral cyclin-cyclin-dependent kinase 6 complexes initiate nuclear DNA replication. Mol Cell Biol 2001; 21: 624–635.

    PubMed  CAS  Google Scholar 

  44. Meraldi P, Lukas J, Fry AM, Bartek J, Nigg EA. Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nat Cell Biol 1999; 1: 88–93.

    PubMed  CAS  Google Scholar 

  45. Krek W, Ewen ME, Shirodkar S, Arany Z, Kaelin WG, Livingston DM. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 1994; 78: 161–172.

    PubMed  CAS  Google Scholar 

  46. Morris L, Allen KE, La Thangue NB. Regulation of E2F transcription by cyclin E-Cdk2 kinase mediated through p300/CBP co-activators. Nat Cell Biol 2000; 2: 232–239.

    PubMed  CAS  Google Scholar 

  47. Leng X, Connell-Crowley L, Goodrich D, Harper JW. S-Phase entry upon ectopic expression of G1 cyclin-dependent kinases in the absence of retinoblastoma protein phosphorylation. Curr Biol 1997; 7: 709–712.

    PubMed  CAS  Google Scholar 

  48. Lukas J, Herzinger T, Hansen K, Moroni MC, Resnitzky D, Helin K, Reed SI, Bartek J. Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dey 1997; 11: 1479–1492.

    CAS  Google Scholar 

  49. Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, Weinberg RA, Sicinski P. Rescue of cyclin DI deficiency by knockin cyclin E. Cell 1999; 97: 767–777.

    CAS  Google Scholar 

  50. Sandhu C, Slingerland J. Deregulation of the cell cycle in cancer. Cancer Detect Prey 2000; 24: 107–118.

    CAS  Google Scholar 

  51. Sherr CJ, Weber JD. The ARF/p53 pathway. Curr Opin Genet Dev 2000; 10: 94–99.

    PubMed  CAS  Google Scholar 

  52. Vidal A, Koff A. Cell-cycle inhibitors: three families united by a common cause. Gene 2000; 247: 1–15.

    PubMed  CAS  Google Scholar 

  53. Bartkova J, Lukas J, Bartek J. Aberrations of the G1- and Gl/S-regulating genes in human cancer. Prog Cell Cycle Res 1997; 3: 211–220.

    PubMed  CAS  Google Scholar 

  54. Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv Cancer Res 1996; 68: 67–108.

    PubMed  CAS  Google Scholar 

  55. Pavletich NP. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J Mol Biol 1999; 287: 821–828.

    PubMed  CAS  Google Scholar 

  56. Morgan DO. Principles of CDK regulation. Nature 1995; 374: 131–134.

    PubMed  CAS  Google Scholar 

  57. Elledge SJ, Harper JW. The role of protein stability in the cell cycle and cancer. Biochim Biophys Acta 1998; 1377: M61 - M70.

    PubMed  CAS  Google Scholar 

  58. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3ß regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12: 3499–3511.

    PubMed  CAS  Google Scholar 

  59. Tyers M, Jorgensen P. Proteolysis and the cell cycle: with this RING I do thee destroy. Curr Opin Genet Dev 2000; 10: 54–64.

    PubMed  CAS  Google Scholar 

  60. Alt JR, Cleveland JL, Hannink M, Diehl JA. Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 2000; 14: 3102–3114.

    PubMed  CAS  Google Scholar 

  61. Pagano M, Ravid K. The cell cycle inhibitor p27 as a prognostic marker in human tumors and a novel target for therapeutic intervention. In: Gutkind JS, ed. Signalling Networks and Cell Cycle Control: The Molecular Basis of Cancer and Other Diseases. Humana Press Inc., Totowa, NJ, 2000, pp. 545–556.

    Google Scholar 

  62. Slingerland J, Pagano M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J Cell Physiol 2000; 183: 10–7.

    PubMed  CAS  Google Scholar 

  63. Matsushime H, Quelle DE, Shurtleff SA, Shibuya M, Sherr CJ, Kato JY. D-type cyclindependent kinase activity in mammalian cells. Mol Cell Biol 1994; 14: 2066–2076.

    PubMed  CAS  Google Scholar 

  64. Stepanova L, Leng X, Harper JW. Analysis of mammalian Cdc37, a protein kinase targeting subunit of heat shock protein 90. Methods Enzymol 1997; 283: 220–229.

    PubMed  CAS  Google Scholar 

  65. Stepanova L, Finegold M, DeMayo F, Schmidt EV, Harper JW. The oncoprotein kinase chaperone CDC37 functions as an oncogene in mice and collaborates with both c-myc and cyclin D1 in transformation of multiple tissues. Mol Cell Biol 2000; 20: 4462–4473.

    PubMed  CAS  Google Scholar 

  66. Cheng M, Olivier P, Diehl JA, Fero M, Roussel MF, Roberts JM, Shen CJ. The p21(Cipl) and p27(Kip1) CDK `inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J 1999; 18: 1571–1583.

    PubMed  CAS  Google Scholar 

  67. Bagui TK, Jackson RJ, Agrawal D, Pledger WJ. Analysis of cyclin D3-cdk4 complexes in fibroblasts expressing and lacking p27(kipl) and p21(cipl). Mol Cell Biol 2000; 20: 8748–8757.

    PubMed  CAS  Google Scholar 

  68. Won KA, Schumacher RJ, Farr GW, Horwich AL, Reed SI. Maturation of human cyclin E requires the function of eukaryotic chaperonin CCT. Mol Cell Biol 1998; 18: 7584–7589.

    CAS  Google Scholar 

  69. Helmbrecht K, Zeise E, Rensing L. Chaperones in cell cycle regulation and mitogenic signal transduction: a review. Cell Prolif 2000; 33: 341–365.

    PubMed  CAS  Google Scholar 

  70. Nakanishi M, Ando H, Watanabe N, Kitamura K, Ito K, Okayama H, Miyamoto T, Agui T, Sasaki M. Identification and characterization of human WeelB, a new member of the weel family of cdk-inhibitory kinases. Genes Cells 2000; 5: 839–847.

    PubMed  CAS  Google Scholar 

  71. Nagahara H, Ezhev sky SA, Vocero-Akbani AM, Kaldis P, Solomon MJ, Dowdy SF. Transforming growth factor beta targeted inactivation of cyclin E:cyclin-dependent kinase 2 (Cdk2) complexes by inhibition of Cdk2 activating kinase activity. Proc Natl Acad Sci USA 1999; 96:14, 961–14, 966.

    Google Scholar 

  72. Kaldis P, Solomon MJ. Analysis of CAK activities from human cells. Eur J Biochem 2000; 267: 4213–4221.

    PubMed  CAS  Google Scholar 

  73. Iavarone A, Massague J. Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15. Nature 1997; 387: 417–422.

    PubMed  CAS  Google Scholar 

  74. Terada Y, Tatsuka M, Jinno S, Okayama H. Requirement for tyrosine phosphorylation of Cdk4 in G1 arrest induced by ultraviolet irradiation. Nature 1995; 376: 358–362.

    PubMed  CAS  Google Scholar 

  75. Reynolds RA, Yem AW, Wolfe CL, Deibel MR Jr, Chidester CG, Watenpaugh KD. Crystal structure of the catalytic subunit of Cdc25B required for G2/M phase transition of the cell cycle. J Mol Biol 1999; 293: 559–568.

    PubMed  CAS  Google Scholar 

  76. Hagopian JC, Kirtley MP, Stevenson LM, Gergis RM, Russo AA, Pavletich NP, Parsons SM, Lew J. Kinetic basis for activation of CDK2/cyclin A by phosphorylation. J Biol Chem 2001; 276: 275–280.

    PubMed  CAS  Google Scholar 

  77. Bartkova J, Zemanova M, Bartek J. Expression of CDK7/CAK in normal and tumor cells of diverse histogenesis, cell-cycle position and differentiation. Ind Cancer 1996; 66: 732–737.

    CAS  Google Scholar 

  78. Parry D, Mahony D, Wills K, Lees E. Cyclin D-CDK subunit arrangement is dependent on the availability of competing INK4 and p21 class inhibitors. Mol Cell Biol 1999; 19: 1775 1783.

    Google Scholar 

  79. Jeffrey PD, Tong L, Pavletich NP. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Genes Dey 2000; 14: 3115–3125.

    CAS  Google Scholar 

  80. Fischer PM, Lane DP. Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem 2000; 7: 1213–1245.

    PubMed  CAS  Google Scholar 

  81. Ball KL, Lain S, Fahraeus R, Smythe C, Lane DP. Cell-cycle arrest and inhibition of Cdk4 activity by small peptides based on the carboxy-terminal domain of p21WAF1. Curr Biol 1997; 7: 71–80.

    PubMed  CAS  Google Scholar 

  82. Fahraeus R, Paramio JM, Ball KL, Lain S, Lane DP. Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from pl6CDKN2/INK4A. Curr Biol 1996; 6: 84–91.

    PubMed  CAS  Google Scholar 

  83. Fahraeus R, Lain S, Ball KL, Lane DP. Characterization of the cyclin-dependent kinase inhibitory domain of the INK4 family as a model for a synthetic tumour suppressor molecule. Oncogene 1998; 16: 587–596.

    PubMed  CAS  Google Scholar 

  84. Cohen BA, Colas P, Brent R. An artificial cell-cycle inhibitor isolated from a combinatorial library. Proc Natl Acad Sci USA 1998; 95:14, 272–14, 277.

    Google Scholar 

  85. Chin KT, Ohki SY, Tang D, Cheng HC, Wang JH, Zhang M. Identification and structure characterization of a Cdk inhibitory peptide derived from neuronal-specific CdkS activator. J Biol Chem 1999; 274: 7120–7127.

    PubMed  CAS  Google Scholar 

  86. Gius DR, Ezhevsky SA, Becker-Hapak M, Nagahara H, Wei MC, Dowdy SF. Transduced p16INK4a peptides inhibit hypophosphorylation of the retinoblastoma protein and cell cycle progression prior to activation of Cdk2 complexes in late G1. Cancer Res 1999; 59: 2577–2580.

    PubMed  CAS  Google Scholar 

  87. Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchya H, Takahashi Y, Masuma R. A new alkaloid AM-2282 of Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. JAntibiot (Tokyo) 1977; 30: 275–282.

    CAS  Google Scholar 

  88. Lawrie AM, Noble ME, Tunnah P, Brown NR, Johnson LN, Endicott JA. Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2. Nat Struct Biol 1997; 4: 796–801.

    PubMed  CAS  Google Scholar 

  89. Kim SH, Schulze-Gahmen U, Brandsen J, de Azevedo Junior WF. Structural basis for chemical inhibition of CDK2. Prog Cell Cycle Res 1996; 2: 137–145.

    PubMed  CAS  Google Scholar 

  90. Otyepka M, Krystof V, Havlicek L, Siglerova V, Strnad M, Koca J. Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2. JMed Chem 2000; 43: 2506–2513.

    CAS  Google Scholar 

  91. Toledo LM, Lydon NB. Structures of staurosporine bound to CDK2 and cAPK-new tools for structure-based design of protein kinase inhibitors. Structure 1997; 5: 1551–1556.

    PubMed  CAS  Google Scholar 

  92. Gussio R, Zaharevitz DW, McGrath CF, Pattabiraman N, Kellogg GE, Schultz C, Link A, Kunick C, Leost M, Meijer L, Sausville EA. Structure-based design modifications of the paullone molecular scaffold for cyclin-dependent kinase inhibition. Anticancer Drug Des 2000; 15: 53–66.

    PubMed  CAS  Google Scholar 

  93. Keskin O, Bahar I, Jernigan RL, Beutler JA, Shoemaker RH, Sausville EA, Covell DG. Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure. Anticancer Drug Des 2000; 15: 79–98.

    PubMed  CAS  Google Scholar 

  94. Legraverend M, Tunnah P, Noble M, Ducrot P, Ludwig O, Grierson DS, Leost M, Meijer L, Endicott J. Cyclin-dependent kinase inhibition by new C-2 alkynylated purine derivatives and molecular structure of a CDK2-inhibitor complex. J Med Chem 2000; 43: 1282 1292.

    Google Scholar 

  95. Murthi KK, Dubay M, McClure C, Brizuela L, Boisclair MD, Worland PJ, Mansuri MM, Pal K. Structure-activity relationship studies of flavopiridol analogues. Bioorg Med Chem Lett 2000; 10: 1037–1041.

    PubMed  CAS  Google Scholar 

  96. Murray AW, Marks D. Can sequencing shed light on cell cycling? Nature 2001; 409: 844–846.

    CAS  Google Scholar 

  97. Hunter T. Signaling-2000 and beyond. Cell 2000; 100: 113–127.

    PubMed  CAS  Google Scholar 

  98. Schulman BA, Lindstrom DL, Harlow E. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin A. Proc Natl Acad Sci USA 1998; 95:10, 453–10, 458.

    Google Scholar 

  99. Kelly BL, Wolfe KG, Roberts JM. Identification of a substrate-targeting domain in cyclin E necessary for phosphorylation of the retinoblastoma protein. Proc Natl Acad Sci USA 1998; 95: 2535–2540.

    CAS  Google Scholar 

  100. Brown NR, Noble ME, Endicott JA, Garman EF, Wakatsuki S, Mitchell E, Rasmussen B, Hunt T, Johnson LN. The crystal structure of cyclin A. Structure 1995; 3: 1235–1247.

    PubMed  CAS  Google Scholar 

  101. Endicott JA, Noble ME, Tucker JA. Cyclin-dependent kinases: inhibition and substrate recognition. Curr Opin Struct Biol 1999; 9: 738–744.

    PubMed  CAS  Google Scholar 

  102. Lee JO, Russo AA, Pavletich NP. Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7. Nature 1998; 391: 859–865.

    PubMed  CAS  Google Scholar 

  103. Takeda DY, Wohlschlegel JA, Dutta A. A bipartite substrate recognition motif for cyclindependent kinases. J Biol Chem 2001; 276: 1993–1997.

    PubMed  CAS  Google Scholar 

  104. Chen YN, Sharma SK, Ramsey TM, Jiang L, Martin MS, Baker K, Adams PD, Bair KW, Kaelin WG Jr. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci USA 1999; 96: 4325–4329.

    PubMed  CAS  Google Scholar 

  105. Tsutsui T, Hesabi B, Moons DS, Pandolfi PP, Hansel KS, Koff A, Kiyokawa H. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip 1) activity. Mol Cell Biol 1999; 19: 7011–7019.

    PubMed  CAS  Google Scholar 

  106. Geng Y, Yu Q, Sicinska E, Das M, Bronson RT, Sicinski P. Deletion of the p27Kipl gene restores normal development in cyclin D1-deficient mice. Proc Natl Acad Sci USA 2001; 98: 194–199.

    PubMed  CAS  Google Scholar 

  107. Tong W, Pollard JW. Genetic evidence for the interactions of cyclin D1 and p27(Kipl) in mice. Mol Cell Biol 2001; 21: 1319–1328.

    PubMed  CAS  Google Scholar 

  108. Harlow E. A research shortcut from a common cold virus to human cancer. Cancer 1996; 78: 558–565.

    PubMed  CAS  Google Scholar 

  109. Hatakeyama M, Weinberg RA. The role of RB in cell cycle control. Prog Cell Cycle Res 1995; 1: 9–19.

    PubMed  CAS  Google Scholar 

  110. Bates S, Peters G. Cyclin D1 as a cellular proto-oncogene. Semin Cancer Biol 1995; 6: 73–82.

    PubMed  CAS  Google Scholar 

  111. DiCiommo D, Gallie BL, Bremner R. Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer. Semin Cancer Biol 2000; 10: 255–269.

    PubMed  CAS  Google Scholar 

  112. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 2000; 16: 168–174.

    PubMed  CAS  Google Scholar 

  113. Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet 1999; 21: 163–167.

    PubMed  CAS  Google Scholar 

  114. Cangi MG, Cukor B, Soung P, Signoretti S, Moreira G Jr, Ranashinge M, Cady B, Pagano M, Loda M. Role of the Cdc25A phosphatase in human breast cancer. J Clin Invest 2000; 106: 753–761.

    PubMed  CAS  Google Scholar 

  115. Ruas M, Brookes S, McDonald NQ, Peters G. Functional evaluation of tumour-specific variants of pl6INK4a/CDKN2A: correlation with protein structure information. Oncogene 1999; 18: 5423–5434.

    PubMed  CAS  Google Scholar 

  116. Sellers WR, Kaelin WG Jr. Role of the retinoblastoma protein in the pathogenesis of human cancer. J Clin Oncol 1997; 15: 3301–3312.

    PubMed  CAS  Google Scholar 

  117. Zheng L, Lee WH. The retinoblastoma gene: a prototypic and multifunctional tumor suppressor. Exp Cell Res 2001; 264: 2–18.

    Google Scholar 

  118. Gille H, Downward J. Multiple ras effector pathways contribute to G(1) cell cycle progression. J Biol Chem 1999; 274:22, 033–22, 040.

    Google Scholar 

  119. Tsatsanis C, Spandidos DA. The role of oncogenic kinases in human cancer. Int J Mol Med 2000; 5: 583–590.

    PubMed  CAS  Google Scholar 

  120. Gjoerup O, Lukas J, Bartek J, Willumsen BM. Rac and Cdc42 are potent stimulators of E2Fdependent transcription capable of promoting retinoblastoma susceptibility gene product hyperphosphorylation. J Biol Chem 1998; 273:18, 812–18, 818.

    Google Scholar 

  121. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177–182.

    PubMed  CAS  Google Scholar 

  122. Lee RJ, Albanese C, Fu M, D’ Amico M, Lin B, Watanabe G, Haines GK III, Siegel PM, Hung MC, Yarden Y, Horowitz JM, Muller WJ, Pestell RG. Cyclin D 1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway. Mol Cell Biol 2000; 20: 672–683.

    PubMed  CAS  Google Scholar 

  123. Massague J, Blain SW, Lo RS. TGF(3 signaling in growth control, cancer, and heritable disorders. Cell 2000; 103: 295–309.

    PubMed  CAS  Google Scholar 

  124. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000; 103: 311–320.

    PubMed  CAS  Google Scholar 

  125. Polakis P. Wnt signaling and cancer. Genes Dey 2000; 14: 1837–1851.

    CAS  Google Scholar 

  126. Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422–426.

    PubMed  CAS  Google Scholar 

  127. Rimerman RA, Gellert-Randleman A, Diehl JA. Wntl and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. JBiol Chem 2000; 275:14, 736–14, 742.

    Google Scholar 

  128. Abate-Shen C, Shen MM. Molecular genetics of prostate cancer. Genes Dey 2000; 14: 2410 2434.

    Google Scholar 

  129. Di Cristofano A, Pandolfi PP. The multiple roles of PTEN in tumor suppression. Cell 2000; 100: 387–390.

    PubMed  Google Scholar 

  130. Bruni P, Boccia A, Baldassarre G, Trapasso F, Santoro M, Chiappetta G, Fusco A, Viglietto G. PTEN expression is reduced in a subset of sporadic thyroid carcinomas: evidence that PTEN-growth suppressing activity in thyroid cancer cells mediated by p27kipl. Oncogene 2000; 19: 3146–3155.

    PubMed  CAS  Google Scholar 

  131. Stambolic V, Mak TW, Woodgett JR. Modulation of cellular apoptotic potential: contributions to oncogenesis. Oncogene 1999; 18: 6094–6103.

    PubMed  CAS  Google Scholar 

  132. Vazquez F, Sellers WR. The PTEN tumor suppressor protein: an antagonist of phosphoinositide 3-kinase signaling. Biochim Biophys Acta 2000; 1470: M21 - M35.

    PubMed  CAS  Google Scholar 

  133. Sun H, Lesche R, Li DM, Liliental J, Zhang H, Gao J, Gavrilova N, Mueller B, Liu X, Wu H. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci USA 1999; 96: 6199–6204.

    PubMed  CAS  Google Scholar 

  134. Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 1999; 21: 99–102.

    PubMed  CAS  Google Scholar 

  135. Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 1997; 7: 679–689.

    PubMed  CAS  Google Scholar 

  136. Brennan P, Babbage JW, Thomas G, Cantrell D. p70(s6k) integrates phosphatidylinositol 3-kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes. Mol Cell Biol 1999; 19: 4729–4738.

    PubMed  CAS  Google Scholar 

  137. Collado M, Medema RH, Garcia-Cao I, Dubuisson ML, Barradas M, Glassford J, Rivas C, Burgering BM, Serrano M, Lam EW. Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kipl. JBiol Chem 2000; 275:21, 96021, 968.

    Google Scholar 

  138. Lasorella A, Noseda M, Beyna M, Iavarone A. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins. Nature 2000; 407: 592–598.

    PubMed  CAS  Google Scholar 

  139. Meijer L, Pondaven P. Cyclic activation of histone HI kinase during sea urchin egg mitotic divisions. Exp Cell Res 1988; 174: 116–129.

    PubMed  CAS  Google Scholar 

  140. Fry D, Garrett MD. Inhibitors of cyclin-dependent kinases as therapeutic agents for the treatment of cancer. Curr Op Onco Endo Meta Invest Drugs 2000; 2: 40–59.

    CAS  Google Scholar 

  141. Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol 1996; 6: 393–397.

    PubMed  CAS  Google Scholar 

  142. Meijer L, Kim SH. Chemical inhibitors of cyclin-dependent kinases. Methods Enzymol 1997; 283: 113–128.

    PubMed  CAS  Google Scholar 

  143. Gray NS, Wodicka L, Thunnissen AM, Norman TC, Kwon S, Espinoza FH, Morgan DO, Barnes G, LeClerc S, Meijer L, Kim SH, Lockhart DJ, Schultz PG. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 1998; 281: 533538.

    Google Scholar 

  144. Kitagawa M, Okabe T, Ogino H, Matsumoto H, Suzuki-Takahashi I, Kokubo T, Higashi H, Saitoh S, Taya Y, Yasuda H, et al. Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase. Oncogene 1993; 8: 2425–2432.

    PubMed  CAS  Google Scholar 

  145. Nishio K, Ishida T, Arioka H, Kurokawa H, Fukuoka K, Nomoto T, Fukumoto H, Yokote H, Saijo N. Antitumor effects of butyrolactone I, a selective cdc2 kinase inhibitor, on human lung cancer cell lines. Anticancer Res 1996; 16: 3387–3395.

    PubMed  CAS  Google Scholar 

  146. Kawakami K, Futami H, Takahara J, Yamaguchi K. UCN-01, 7-hydroxyl-staurosporine, inhibits kinase activity of cyclin-dependent kinases and reduces the phosphorylation of the retino-blastoma susceptibility gene product in A549 human lung cancer cell line. Biochem Biophys Res Commun 1996; 219: 778–783.

    PubMed  CAS  Google Scholar 

  147. Akiyama T, Yoshida T, Tsujita T, Shimizu M, Mizukami T, Okabe M, Akinaga S. G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cip l/WAF1/Sdi l in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res 1997; 57: 1495–1501.

    PubMed  CAS  Google Scholar 

  148. Hsueh CT, Chiu CF, Schwartz GK. UCN-01 suppresses E2F-1 mediated by ubiquitin-proteosome dependent degradation. Amer Soc of Clin Oncol 2000; 19: 798.

    Google Scholar 

  149. Akinaga S, Nomura K, Gomi K, Okabe M. Enhancement of antitumor activity of mitomycin C in vitro and in vivo by UCN-01, a selective inhibitor of protein kinase C. Cancer Chemother Pharmacol 1993; 32: 183–189.

    CAS  Google Scholar 

  150. Bunch RT, Eastman A. Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2-checkpoint inhibitor. Clin Cancer Res 1996; 2: 791–797.

    PubMed  CAS  Google Scholar 

  151. Hsueh CT, Kelsen D, Schwartz GK. UCN-01 suppresses thymidylate synthase gene expression and enhances 5-fluorouracil-induced apoptosis in a sequence-dependent manner. Clin Cancer Res 1998; 4: 2201–2206.

    PubMed  CAS  Google Scholar 

  152. Fuse E, Tanii H, Kurata N, Kobayashi H, Shimada Y, Tamura T, Sasaki Y, Tanigawara Y, Lush RD, Headlee D, Figg WD, Arbuck SG, Senderowicz AM, Sausville EA, Akinaga S, Kuwabara T, Kobayashi S. Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human alphal-acid glycoprotein. Cancer Res 1998; 58: 3248–3253.

    PubMed  CAS  Google Scholar 

  153. Senderowicz AM, Headlee D, Lush R, Arbuck S, Bauer K, Figg WD, Murgo A, Inoue K, Kuwabara T, Sausville EA. Phase I trial of infusional UCN-01, a novel protein kinase inhibitor, in patients with refractory neoplasms. Amer Soc of Clin Oncol 1999; 18: 612.

    Google Scholar 

  154. l 54. Sedlacek HH, Czeck J, Naik R, Kaur G, Worland P, Losiewicz M, Parker B, Carlson B, Smith A, Senderowicz A, Sausville EA. Flavopiridol (L86–8275, NSC-649890), a new kinase inhibitor for tumor therapy. Int J Oncol 1996; 9: 1143–1168.

    Google Scholar 

  155. Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase CDK 2 and CDK4 in human breast carcinoma cells. Cancer Res 1996; 56: 2973–2978.

    PubMed  CAS  Google Scholar 

  156. Losiewicz MD, Carlson BA, Kaur G, Sausville EA, Worland PJ. Potent inhibition of CDC2 kinase activity by the flavonoid L86–8275. Biochem Biophys Res Commun 1994; 201: 589–595.

    PubMed  CAS  Google Scholar 

  157. Schwartz GK, Farsi K, Maslak P, Kelsen DP, Spriggs D. Potentiation of apoptosis by flavopiridol in mitomycin-C-treated gastric and breast cancer cells. Clin Cancer Res 1997; 3: 1467–1472.

    PubMed  CAS  Google Scholar 

  158. Arguello F, Alexander M, Sterry JA, Tudor G, Smith EM, Kalavar NT, Greene JF Jr, Koss W, Morgan CD, Stinson SF, Siford TJ, Alvord WG, Klabansky RL, Sausville EA. Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity In vivo against human leukemia and lymphoma xenografts. Blood 1998; 91: 2482–2490.

    PubMed  CAS  Google Scholar 

  159. Czeck J, Hoffman D, Naik R, Sedlacek H. Antitumoral activity of flavone L86–8275. Int J Oncol 1995; 6: 31–36.

    Google Scholar 

  160. Drees M, Dengler WA, Roth T, Labonte H, Mayo J, Malspeis L, Grever M, Sausville EA, Fiebig HH. Flavopiridol (L86–8275): selective antitumor activity in vitro and activity in vivo for prostate carcinoma cells. Clin Cancer Res 1997; 3: 273–279.

    PubMed  CAS  Google Scholar 

  161. Kaur G, Stetler-Stevenson M, Sehers S, Worland P, Sedlacek H, Myers C, Czech J, Naik R, Sausville E. Growth inhibition with reversible cell cycle arrest of carcinoma cells by flavone L86–8275. J Natl Cancer Inst 1992; 84: 1736–1740.

    PubMed  CAS  Google Scholar 

  162. Konig A, Schwartz GK, Mohammad RM, Al-Katib A, Gabrilove JL. The novel cyclindependent kinase inhibitor flavopiridol downregulates Bc1–2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines. Blood 1997; 90: 4307–4312.

    PubMed  CAS  Google Scholar 

  163. Parker BW, Kaur G, Nieves-Neira W, Taimi M, Kohlhagen G, Shimizu T, Losiewicz MD, Pommier Y, Sausville EA, Senderowicz AM. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 1998; 91: 458–465.

    PubMed  CAS  Google Scholar 

  164. Schrump DS, Matthews W, Chen GA, Mixon A, Altorki NK. Flavopiridol mediates cell cycle arrest and apoptosis in esophageal cancer cells. Clin Cancer Res 1998; 4: 2885–2890.

    PubMed  CAS  Google Scholar 

  165. Bible KC, Kaufmann SH. Cytotoxic synergy between flavopiridol (NSC 649890, L86–8275) and various antineoplastic agents: the importance of sequence of administration. Cancer Res 1997; 57: 3375–3380.

    PubMed  CAS  Google Scholar 

  166. Senderowicz AM, Headlee D, Stinson SF, Lush RM, Kalil N, Villalba L, Hill K, Steinberg SM, Figg WD, Tompkins A, Arbuck SG, Sausville EA. Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms. J Clin Oncol 1998; 16: 2986–2999.

    PubMed  CAS  Google Scholar 

  167. Senderowicz AM. Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs 1999; 17: 313–320.

    PubMed  CAS  Google Scholar 

  168. Thomas J, Cleary J, Tutsch K. Phase I clinical and pharmacokinetic trial of flavopriridol. Proc Annu Amer Asso Cancer Res 1997; 38: 1497.

    Google Scholar 

  169. Lush RM, Stinson S, Senderowicz AM. Flavopiridol pharmacokinetics suggest enterohepatic circulation. Clin Pharmacol Ther 1998; 61: 145–149.

    Google Scholar 

  170. Jager W, Zembsch B, Wolschann P, Pittenauer E, Senderowicz AM, Sausville EA, Sedlacek HH, Graf J, Thalhammer T. Metabolism of the anticancer drug flavopiridol, a new inhibitor of cyclin dependent kinases, in rat liver. Life Sci 1998; 62: 1861–1873.

    PubMed  CAS  Google Scholar 

  171. Ramirez J, Iyer L, Lush RM. In vitro glucorinidation of flavopiridol (NSC-649890) (Flavo) by human liver microsomes. Clin Pharmacol Ther 1998; 63: 149–155.

    Google Scholar 

  172. Schwartz GK, Kaubisch A, Saltz L, Ilson D, O’Reilly E, Barazzuol J, Endres S, Soltz M, Tong W, Spriggs S, Kelsen DP. Phase I trial of sequential paclitaxel and the cyclin-dependent kinase inhibitor flavopiridol. Amer Soc Clin Oncol 1999; 18: 614.

    Google Scholar 

  173. Stadler WM, Vogelzang NJ, Amato R, Sosman J, Taber D, Liebowitz D, Vokes EE. Flavopiridol, a novel cyclin-dependent kinase inhibitor, in metastatic renal cancer: a University of Chicago Phase II Consortium study. J Clin Oncol 2000; 18: 371–375.

    PubMed  CAS  Google Scholar 

  174. Shapiro G, Patterson A, Lynch C, Lucca J, Anderson I, Boral A, Elias A, Lu H, Salgia R, Skarin A, Panek-Clark C, McKenna R, Rabin M, Vasconcelles M, Eder P, Supko J. A phase II trail of flavopiridol in patients with stage IV non-small cell lung cancer. Amer Soc Clin Oncol 1999; 18: 2013.

    Google Scholar 

  175. Benett P, Mani S, O’Rilly S, Wright J, Schilsky RL, Vokes EE, Grochow L. Phase II trail of flavopiridol in metastatic colorectal cancer: preliminary results. Amer Soc Clin Oncol 1999; 18: 1065.

    Google Scholar 

  176. Werner JL, Kelsen DP, Karpeh M, Inzeo D, Barazzuol J, Sugarman A, Schwartz GK. The cyclin-dependent kinase inhibitor flavopiridol is an active and unexpectedly toxic agent in advanced gastric cancer. Amer Soc Clin Oncol 1998; 17: 896.

    Google Scholar 

  177. Wright J, Blatner GL, Cheson BD. Clinical trials referral resource. Clinical trials of flavopiridol. Oncology (Huntingt) 1998; 12: 1018, 1023–1024.

    Google Scholar 

  178. Zaharevitz DW, Gussio R, Leost M, Senderowicz AM, Lahusen T, Kunick C, Meijer L, Sausville EA. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases. Cancer Res 1999; 59: 2566–2569.

    PubMed  CAS  Google Scholar 

  179. Schultz C, Link A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L, Kunick C. Paullones, a series of cyclin-dependent kinase inhibitors: synthesis, evaluation of CDK1/ cyclin B inhibition, and in vitro antitumor activity. J Med Chem 1999; 42: 2909–2919.

    PubMed  CAS  Google Scholar 

  180. Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM, Bibb JA, Snyder GL, Greengard P, Zaharevitz DW, Gussio R, Senderowicz AM, Sausville EA, Kunick C, Meijer L. Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur J Biochem 2000; 267: 5983–5994.

    PubMed  CAS  Google Scholar 

  181. Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol 1999; 1: 60–67.

    PubMed  CAS  Google Scholar 

  182. Barvian M, Boschelli DH, Cossrow J, Dobrusin E, Fattaey A, Fritsch A, Fry D, Harvey P, Keller P, Garrett M, La F, Leopold W, McNamara D, Quin M, Trumpp-Kallmeyer S, Toogood P, Wu Z, Zhang E. Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. J Med Chem 2000; 43: 4606–4616.

    PubMed  CAS  Google Scholar 

  183. Boschelli DH, Dobrusin EM, Doherty AM, Fattacy A, Fry DW, Barvian MR, Kallmyeyer ST, Wu Z. Pyridi [2,3-d]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation. USA: Parke-Davis, 1998. Patent #WO-09833798.

    Google Scholar 

  184. Fry DW, Bedford DC, Harvey PH, Fritsch A, Keller PR, Wu Z, Dobrusin E, Leopold WR, Fattaey A, Garrett MD. Cell cycle and biochemical effects of PD 0183812; a potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. JBiol Chem 2001; 276:16, 617–16, 623.

    Google Scholar 

  185. Klutchko SR, Hamby JM, Boschelli DH, Wu Z, Kraker AJ, Amar AM, Hartl BG, Shen C, Klohs WD, Steinkampf RW, Driscoll DL, Nelson JM, Elliott WL, Roberts BJ, Stoner CL, Vincent PW, Dykes DJ, Panek RL, Lu GH, Major TC, Dahring TK, Hallak H, Bradford LA, Showalter HD, Doherty AM. 2-Substituted aminopyrido[2,3-d]pyrimidin-7(8H)-ones. structure-activity relationships against selected tyrosine kinases and in vitro and in vivo anticancer activity. J Med Chem 1998; 41:3276–3292.

    Google Scholar 

  186. Garrett MD, Fry DW, Quinn M, Crosier W, Dobrusin E, Leopold WR, Fattaey A. A chemical inhibitor of CDK4/Cyclin D1 kinase activity. Keystone Symposia 1998, p. 40.

    Google Scholar 

  187. Nelson JM, Boschelli D, Dobrusin EM, Wu Z, Fattaey A, Garrett MD, Keller PR, Leopold WR, Fry DW. Cell Cycle and biological effects of PD-171851, a specific inhibitor of cyclindependent kinase 4 (CDK4). Keystone Symposia 1998, p. 67.

    Google Scholar 

  188. Kent LL, Hull-Campbell NE, Lau T, Wu JC, Thompson SA, Nori M. Characterization of novel inhibitors of cyclin-dependent kinases. Biochem Biophys Res Commun 1999; 260: 768–774.

    PubMed  CAS  Google Scholar 

  189. Lane ME, Yu B, Rice A, Sun L, Lipson K, Tang C, McMahon G, Wadler S. Effects of CDK inhibitor SU9516 on human colorectal cancer cells. Proc Amer Assoc Cancer Res 2000; 41: 1586.

    Google Scholar 

  190. Davis ST, Dickerson SH, Frye SV, Harris PA, Hunter RN, Kuyper LF, Lackey KE, Luzzio MJ, Veal JM, Walker DH. Substituted oxindole derivatives as protein tyrosine kinase and as serine/threonine kinase inhibitors. USA: Glaxo-Wellcome, 1999. Patent #WO-09915500.

    Google Scholar 

  191. Walker DH, Luzzio M, Veal J, Dold K, Edelstein M, Parker P, Rusnak D, Emerson D, Miller C, Onori J, Bramson HN, Harris P, Hunter R, Dickerson S, Kuyper L. The novel cyclin dependent kinase inhibitors, GW-5181 and GW-9499 regulate cell cycle progression and induce tumor selective cell death. Proc Annual Amer Asso Cancer Res 1999; 40: 724.

    Google Scholar 

  192. Chong WK, Chu SS, Duvadie RR, Li L, Xiao W, Yang Y. 4-Aminothiazole derivatives, their preparation and their use as inhibitor of cyclin-dependent kinases. USA: Agouron Pharmaceuticals, 1999. Patent #WO-09921845.

    Google Scholar 

  193. Duvadie RK, Chong WKM, Li L, Chu SS, Yang YM, Nonomiya J, Tucker KD, Lewis CT, Knighton DR, Ferre RA, Lundgren K, Koudrakova T, Escobar J, Price SM, Huber A, Sisson W, Aust RM, Verkhivker GM, Schaffer L, Rose PW. Novel ATP-site cyclin-dependent kinase (CDK) inhibitors: selective CDK inhibitors. Amer Chem Soc Meeting. MEDI, 1999, p. 214.

    Google Scholar 

  194. Lundgren K, Price SM, Escobar J, Huber A, Chong W, Li L, Duvadie R, Chu SS, Yang Y, Nonomiya J, Tucker K, Knighton D, Ferre R, Lewis C. Diaminothiazoles: potent, selective cyclin-dependent kinase inhibitors with anti-tumor efficacy. Clin Cancer Res 1999; 5: 37553762.

    Google Scholar 

  195. Dhingra U, Ken R, Fishteyn D, Kratzeisen C, Tamborinin B, Tarby C, Thomas M, Bertasso A, Mistry N, Kraeft SK, Chen LB, Foley L. Characterization of in vitro antiproliferative activity of Ro 31–7453, a new cell cycle inhibitor. Proc Amer Asso Cancer Res 2000; 41: 198.

    Google Scholar 

  196. Dhingra U, Luistro LL, Mortnsen JH, Sampeur PS, Butler J, Brunda M, Bailey C, Shah N, Phuapradit W, Holden S, Chen LB, Truitt GA, Manzotti C, Pezzoni G, Ritland S. Ro 31–7453 has in-vivo antitumor activity against human xenograft and syngeneic tumor models. Proc Amer Asso Cancer Res 2000; 41: 219.

    Google Scholar 

  197. Dhingra U, Mortensen JH, Luistro LL, Sapeur PS. Evaluation of effects of dose and schedule on efficacy and toxicity of orally administered Ro 31–7453 in tumor bearing nude mice. Proc Amer Asso Cancer Res 2000; 41: 219.

    Google Scholar 

  198. Dhingra U, Thomas M, Bertasso A, Mistry N, Weber G, Luistro L, Mortensen J, Singh P, Fotouhi N, Lovey A, Chang D, Yin H, Ke J. Identification and preclinical characterization of metabolites of Ro 31–7453, a new cell-cycle inhibitor. Proc Amer Asso Cancer Res 2000; 41: 199.

    Google Scholar 

  199. Soignet S, Bienvenu B, Pezzuli S, Ng K, Vongphrachanh P, Breimer L, Jianguo Z, Dhingra K, Huber MH, Spriggs D. Clinical and pharmacokinetic study of a novel cell-cycle inhibitor (Ro 31–7453) in patients with solid tumors. Proc Amer Asso Cancer Res 2000; 41: 3884.

    Google Scholar 

  200. Elledge SJ, Spottswood MR. A new human p34 protein kinase, CDK2, identified by complementation of a cdc28 mutation in Saccharomyces cerevisiae, is a homolog of Xenopus Egl. EMBO J 1991; 10: 2653–2659.

    PubMed  CAS  Google Scholar 

  201. Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM, Arnold A. A novel cyclin encoded by a bcll-linked candidate oncogene. Nature 1991; 350: 512–515.

    PubMed  CAS  Google Scholar 

  202. Meyerson M, Enders GH, Wu CL, Su LK, Gorka C, Nelson C, Harlow E, Tsai LH. A family of human cdc2-related protein kinases. EMBO J 1992; 11: 2909–2917.

    PubMed  CAS  Google Scholar 

  203. Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, Sherr CJ. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 1992; 71: 323–334.

    PubMed  CAS  Google Scholar 

  204. Leclerc S, Gamier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L. Indirubins inhibit glycogen synthase kinase-3beta and CDK5/p25, Two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s Disease. A property common to most cyclin-dependent kinase inhibitors? JBiol Chem 2001; 276: 251–260.

    CAS  Google Scholar 

  205. Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM, Peterlin BM, Price DH. Flavopiridol inhibits P-TEFb and blocks HIV-1 replication. J Biol Chem 2000; 275:28, 345–28, 348.

    Google Scholar 

  206. Bible KC, Bible RH Jr, Kottke TJ, Svingen PA, Xu K, Pang YP, Hajdu E, Kaufmann SH. Flavopiridol binds to duplex DNA. Cancer Res 2000; 60: 2419–2428.

    PubMed  CAS  Google Scholar 

  207. Graves PR, Yu L, Schwarz JK, Gales J, Sausville EA, O’Connor PM, Piwnica-Worms H. The Chkl protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J Biol Chem 2000; 275: 5600–5605.

    PubMed  CAS  Google Scholar 

  208. Breton JJ, Chabot-Fletcher MC. The natural product hymenialdisine inhibits interleukin-8 production in U937 cells by inhibition of nuclear factor-kappaB. J Pharmacol Exp Ther 1997; 282: 459–466.

    PubMed  CAS  Google Scholar 

  209. Maly DJ, Choong IC, Ellman JA. Combinatorial target-guided ligand assembly: identification of potent subtype-selective c-Src inhibitors. Proc Natl Acad Sci USA 2000; 97: 2419 2424.

    Google Scholar 

  210. Erlanson DA, Braisted AC, Raphael DR, Randal M, Stroud RM, Gordon EM, Wells JA. Site-directed ligand discovery. Proc Natl Acad Sci USA 2000; 97: 9367–9372.

    PubMed  CAS  Google Scholar 

  211. Burack WR, Shaw AS. Signal transduction: hanging on a scaffold. Curr Opin Cell Bio12000; 12: 211–216.

    Google Scholar 

  212. Way JC. Covalent modification as a strategy to block protein-protein interactions with small-molecule drugs. Curr Opin Chem Biol 2000; 4: 40–46.

    PubMed  CAS  Google Scholar 

  213. Knockaert M, Gray N, Damiens E, Chang YT, Grellier P, Grant K, Fergusson D, Mottram J, Soete M, Dubremetz JF, Le Roch K, Doerig C, Schultz P, Meijer L. Intracellular targets of cyclin-dependent kinase inhibitors: identification by affinity chromatography using immobilised inhibitors. Chem Biol 2000; 7: 411–422.

    PubMed  CAS  Google Scholar 

  214. Haab BB, Dunham MJ, Brown PO. Protein microarrays for highly parallel detection and quantitation of specific proteins and antibodies in complex solutions. Genomebiology 2000; http://genomebiology.com/2001/2/2/research/0004.

    Google Scholar 

  215. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge 0, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752.

    PubMed  CAS  Google Scholar 

  216. Scherf U, Ross DT, Waltham M, Smith LH, Lee JK, Tanabe L, Kohn KW, Reinhold WC, Myers TG, Andrews DT, Scudiero DA, Eisen MB, Sausville EA, Pommier Y, Botstein D, Brown PO, Weinstein JN. A gene expression database for the molecular pharmacology of cancer. Nat Genet 2000; 24: 236–244.

    PubMed  CAS  Google Scholar 

  217. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Staudt LM, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.

    PubMed  CAS  Google Scholar 

  218. Davis ST, Benson BG, Bramson HN, Chapman DE, Dickerson SH, Dold KM, Eberwein DJ, Edelstein M, Frye SV, Gampe RT Jr, Griffin RJ, Harris PA, Hassell AM, Holmes WD, Hunter RN, Knick VB, Lackey K, Lovejoy B, Luzzio MJ, Murray D, Parker P, Rocque WJ, Shewchuk L, Veal JM, Walker DH, KuyperLF. Prevention of Chemotherapy-Induced Alopecia in Rats by CDK Inhibitors. Science 2001; 291: 134–137.

    PubMed  CAS  Google Scholar 

  219. Osuga H, Osuga S, Wang F, Fetni R, Hogan MJ, Slack RS, Hakim AM, Ikeda JE, Park DS. Cyclin-dependent kinases as a therapeutic target for stroke. Proc Natl Acad Sci USA 2000; 97:10, 254–10, 259.

    Google Scholar 

  220. Alvarez A, Toro R, Caceres A, Maccioni RB. Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death. FEBS Lett 1999; 459: 421–426.

    PubMed  CAS  Google Scholar 

  221. Modiano JF, Mayor J, Ball C, Fuentes MK, Linthicum DS. CDK4 expression and activity are required for cytokine responsiveness in T cells. J Immunol 2000; 165: 6693–6702.

    PubMed  CAS  Google Scholar 

  222. Wolf G. Cell cycle regulation in diabetic nephropathy. Kidney Int 2000; 58: 59–66.

    Google Scholar 

  223. Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS. Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F•DP, in B-amyloid-induced neuronal death. J Biol Chem 1999; 274:19, 011–19, 016.

    Google Scholar 

  224. Meijer L, Thunnissen AM, White AW, Gamier M, Nikolic M, Tsai LH, Walter J, Cleverley KE, Salinas PC, Wu YZ, Biernat J, Mandelkow EM, Kim SH, Pettit GR. Inhibition of cyclindependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. Chem Biol 2000; 7: 51–63.

    PubMed  CAS  Google Scholar 

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Authors
  1. R. Nagaraja Rao
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  2. Bharvin K. R. Patel
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Editor information

Editors and Affiliations

  1. Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland

    Nicholas B. La Thangue (Cathcart Professor of Biochemistry, Chief Scientific Officer) (Cathcart Professor of Biochemistry, Chief Scientific Officer)

  2. Prolifix Ltd., Abingdon, Oxon, UK

    Nicholas B. La Thangue (Cathcart Professor of Biochemistry, Chief Scientific Officer) (Cathcart Professor of Biochemistry, Chief Scientific Officer)

  3. Oxford Glycosciences Ltd., Abingdon, Oxon, UK

    Lasantha R. Bandara

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© 2002 Springer Science+Business Media New York

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Rao, R.N., Patel, B.K.R. (2002). Cyclin-Dependent Kinases and Their Small-Molecule Inhibitors in Cancer Therapy. In: La Thangue, N.B., Bandara, L.R. (eds) Targets for Cancer Chemotherapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-153-4_8

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  • DOI: https://doi.org/10.1007/978-1-59259-153-4_8

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-263-6

  • Online ISBN: 978-1-59259-153-4

  • eBook Packages: Springer Book Archive

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