The AAPS Journal

, Volume 8, Issue 1, pp E204–E221 | Cite as

Selectivity and potency of cyclin-dependent kinase inhibitors

  • Jayalakshmi Sridhar
  • Nagaraju Akula
  • Nagarajan PattabiramanEmail author


Members of the cyclin-dependent kinase (CDK) family play key roles in various cellular processes. There are 11 members of the CDK family known till now. CDKs are activated by forming noncovalent complexes with cyclins such as A-, B-, C-, D- (D1, D2, and D3), and E-type cyclins. Each isozyme of this family is responsible for particular aspects (cell signaling, transcription, etc) of the cell cycle, and some of the CDK isozymes are specific to certain kinds of tissues. Aberrant expression and overexpression of these kinases are evidenced in many disease conditions. Inhibition of isozymes of CDKs specifically can yield beneficiary treatment modalities with minimum side effects. More than 80 3-dimensional structures of CDK2, CDK5, and CDK6 complexed with inhibitors have been published. This review provides an understanding of the structural aspects of CDK isozymes and binding modes of various known CDK inhibitors so that these kinases can be better targeted for drug discovery and design. The amino acid residues that constitute the cyclin binding region, the substrate binding region, and the area around the adenosine triphosphate (ATP) binding site have been compared for CDK isozymes. Those amino acids at the ATP binding site that could be used to improve the potency and subtype specificity have been described.


cyclin-dependent kinases cell cycle CDK inhibitors structure-based design/discovery ATP binding site cyclin binding peptides 


  1. 1.
    Noble MEM, Endicott JA, Johnson LN. Protein kinase inhibitors: insights into drug design from structure.Science. 2004;303:1800–1805.PubMedCrossRefGoogle Scholar
  2. 2.
    Karin M, Hunter T. Transcriptional control by protein phosphorylation: signal transmission from the cell surface to the nucleus.Curr Biol. 1995;5:747–757.PubMedCrossRefGoogle Scholar
  3. 3.
    Johnson GL, Lapadat R. Mitogen activated protein kinase pathways mediated by ERK, JNK and p38 protein kinases.Science. 2002;298:1911–1912.PubMedCrossRefGoogle Scholar
  4. 4.
    Fabbro D, Ruetz S, Buchdunger E. et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs.Pharmacol Ther. 2002;93:79–98.PubMedCrossRefGoogle Scholar
  5. 5.
    Geschwind DH. Tau phosphorylation, tangles, and neurodegeneration: the chicken or the egg.Neuron. 2003;40:457–460.PubMedCrossRefGoogle Scholar
  6. 6.
    Cohen P. Protein kinases: the major drug targets of the twenty-first century?Nat Rev Drug Discov. 2002;1:309–315.PubMedCrossRefGoogle Scholar
  7. 7.
    Dancey J, Sausville EA. Issues and progress with protein kinase inhibitors for cancer treatment.Nat Rev Drug Discov. 2003;2:296–313.PubMedCrossRefGoogle Scholar
  8. 8.
    Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome.Science. 2001;291:1304–1351.PubMedCrossRefGoogle Scholar
  9. 9.
    Manning G, Whyte DB, Martinez R, et al. The protein kinase complement of the human genome.Science. 2002;298:1912–1934.PubMedCrossRefGoogle Scholar
  10. 10.
    Pines J. Cyclins and cyclin-dependent kinases: theme and variations.Adv Cancer Res. 1995;66:181–212.PubMedCrossRefGoogle Scholar
  11. 11.
    Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors.Annu Rev Cell Dev Biol. 1997;13:261–291.PubMedCrossRefGoogle Scholar
  12. 12.
    Paglini G, Caceres A. The role of the Cdk5-p35 kinase in neuronal development.Eur J Biochem. 2001;268:1528–1533.PubMedCrossRefGoogle Scholar
  13. 13.
    Akoulitchev S, Chuikov S, Reinberg D. TFIIH is negatively regulated by cdk8-containing mediator complexes.Nature. 2000;407:102–106.PubMedCrossRefGoogle Scholar
  14. 14.
    Sano M, Schneider MD. Cyclins that don't cycle: cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size.Cell Cycle. 2003;2:99–104.PubMedCrossRefGoogle Scholar
  15. 15.
    Shuttleworth J. The regulation and functions of cdk7.Prog Cell Cycle Res. 1995;1:229–240.PubMedCrossRefGoogle Scholar
  16. 16.
    Kasten M, Giordano A. Cdk 10, a Cdc2-related kinase, associates with the Ets2 transcription factor and modulates its transactivation activity.Oncogene. 2001;20:1832–1838.PubMedCrossRefGoogle Scholar
  17. 17.
    Ren S, Rollins BJ. Cyclin C/Cdk3 promotes Rb-dependent G0 exit.Cell 2004;117:239–251.PubMedCrossRefGoogle Scholar
  18. 18.
    Papst PJ, Sugiyama H, Nagasawa M, et al. Cdc2-cyclin B phosphorylates p70 S6 kinase on Ser411 at mitosis.J Biol Chem. 1998;273: 15077–15084.PubMedCrossRefGoogle Scholar
  19. 19.
    Long JJ, Leresche A, Kriwacki RW, et al. Repression of TFIIH transcriptional activity and TFIIH-associated cdk7 kinase activity at mitosis.Mol Cell Biol. 1998;18:1467–1476.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Nigg EA. Cyclin-dependent kinase 7: at the cross-roads of transcription, DNA repair and cell cycle control?Curr Opin Cell Biol. 1996;8:312–317.PubMedCrossRefGoogle Scholar
  21. 21.
    Dowdy SF, Hinds PW, Louie K, et al. Physical interaction of the retinoblastoma protein with human D cyclins.Cell. 1993;73:499–511.PubMedCrossRefGoogle Scholar
  22. 22.
    Luo RX, Postigo AA, Dean DC. Rb interacts with histone deacetylase to repress transcription.Cell. 1998;92:463–473.PubMedCrossRefGoogle Scholar
  23. 23.
    Pan W, Sun T, Hoess R, et al. Defining the minimal portion of the retinoblastoma protein that serves as an efficient substrate for CDK4 kinase/cyclin D1 complex.Carcinogenesis. 1998;19:765–769.PubMedCrossRefGoogle Scholar
  24. 24.
    Adams PD. Regulation of retinoblastoma tumor suppressor protein by cyclin/CDKs.Biochim Biophys Acta. 2001;1471:M123-M133.PubMedGoogle Scholar
  25. 25.
    Harbour JW, Dean DC. The pRb/E2F pathway: expanding roles and emerging paradigms.Genes Dev. 2000;14:2393–2409.PubMedCrossRefGoogle Scholar
  26. 26.
    Sherr CJ. Cancer cell cycles revisited.Cancer Res. 2000;60:3689–3695.PubMedGoogle Scholar
  27. 27.
    Sherr CJ, Roberts JM. Cdk inhibitors: positive and negative regulators of G1-phase progression.Genes Dev. 1999;13:1501–1512.PubMedCrossRefGoogle Scholar
  28. 28.
    Ekholm SV, Reed SI. Regulation of G1 cyclin-dependent kinases in the mammalian cell cycle.Curr Opin Cell Biol. 2000;12:676–684.PubMedCrossRefGoogle Scholar
  29. 29.
    Lee MH, Yang HY. Negative regulators of cyclin-dependent kinases and their roles in cancers.Cell Mol Life Sci. 2001;58:1907–1922.PubMedCrossRefGoogle Scholar
  30. 30.
    Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of p27Kipl, a cyclin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals.Cell. 1994;78:59–66.PubMedCrossRefGoogle Scholar
  31. 31.
    Russo AA, Jeffery PD, Patten AK, et al. Crystal structure of the p27Kipl cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex.Nature. 1996;382:325–331.PubMedCrossRefGoogle Scholar
  32. 32.
    Cheng M, Olivier P, Diehl JA, et al. The p21 (Cip1) and p27(Kip1) CDK ‘inhibitors’ are essential activators of cyclin D-dependent kinases in murine fibroblasts.EMBO J. 1999;18:1571–1583.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Weinstein IB, Zhou P. Defects in cell cycle control genes in human cancer. In: Bertino [initial?], ed.Encyclopedia of Cancer. Vol 1. New York, NY: Academic Press, 1997:256–267.Google Scholar
  34. 34.
    Sgambato A, Flamini G, Cittadini A, et al. Abnormalities in cell cycle control in cancer and their clinical implications.Tumori. 1998;84:421–433.PubMedGoogle Scholar
  35. 35.
    D'Amico M, Wu K, Fu M, et al. The Inhibitor of Cyclin-dependent Kinase 4a/Alternative Reading Frame (INK 4a/ARF) Locus Encoded Proteins p16INK4a and p19ARF Repress Cyclin D1 Transcription through distinct cis elements.Cancer Res. 2004;64:4122–4130.PubMedCrossRefGoogle Scholar
  36. 36.
    Miliani de Marval PL, Macias E, Rounbehler R, et al. Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues.Mol Cell Biol. 2004;24:7538–7547.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Galaktionov K, Lee AK, Exkstein J, et al. Cdc25 phosphatases as potential human oncogenes.Science. 1995;269:1575–1577.PubMedCrossRefGoogle Scholar
  38. 38.
    Wu W, Fan Y-H, Kemp BL, et al. Over-expression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with over-expression of c-myc.Cancer Res. 1998;58:4082–4085.PubMedGoogle Scholar
  39. 39.
    Park DS, Farinelli SE, Greene LA. Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons.J Biol Chem. 1996;271: 8161–8169.PubMedCrossRefGoogle Scholar
  40. 40.
    Dhavan R, Tsai LH. A decade of CDK5.Nat Rev Mol Cell Biol. 2001;2:749–759.PubMedCrossRefGoogle Scholar
  41. 41.
    Gupta A, Tsai LH. Cyclin-dependent kinase 5 and neuronal migration in the neocortex.Neurosignals. 2003;12:173–179.PubMedCrossRefGoogle Scholar
  42. 42.
    Ko J, Humbert S, Bronson RT, et al. p35 and p39 are essential for cdk5 function during neurodevelopment.J Neurosci. 2001;21:6758–6771.PubMedGoogle Scholar
  43. 43.
    Cheng K, Ip NY. Cdk5: a new player at synapses.Neurosignals. 2003;12:180–190.PubMedCrossRefGoogle Scholar
  44. 44.
    Bibb JA. Role of cdk5 in neuronal signaling, plasticity and drug abuse.Neurosignals. 2003;12:191–199.PubMedCrossRefGoogle Scholar
  45. 45.
    Nguyen MD, Julien JP. Cyclin-dependent kinase 5 in amyotrophic lateral sclerosis.Neurosignals. 2003;12:215–220.PubMedCrossRefGoogle Scholar
  46. 46.
    Lau LF, Ahlijanian MK. Role of CDK5 in the pathogenesis of Alzheimer's disease.Neurosignals. 2003;12:209–214.PubMedCrossRefGoogle Scholar
  47. 47.
    Smith PD, Crocker SJ, Jackson-Lewis V, et al. Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease.Proc Natl Acad Sci USA. 2003;100; 13650–13655.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Bu B, Li J, Davies P, et al. Deregulation of CDK5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model.J Neurosci. 2002;22:6515–6525.PubMedGoogle Scholar
  49. 49.
    Morgan DO. The dynamics of cyclin-dependent kinase structure.Curr Opin Cell Biol. 1996;8:767–772.PubMedCrossRefGoogle Scholar
  50. 50.
    Chen J, Saha P, Kornbluth S, et al. Cyclin binding motifs are essential for the function of p21CIP1.Mol Cell Biol. 1996;16:4673–4682.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    De Bondt HL, Rosenblatt J, Jancarik J, et al. Crystal structure of cyclin-dependent kinase 2.Nature. 1993;363:595–602.PubMedCrossRefGoogle Scholar
  52. 52.
    Jeffrey PD, Russo AA, Polyak K, et al. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex.Nature 1995;376:313–320.PubMedCrossRefGoogle Scholar
  53. 53.
    Higgins DG, Bleasby AJ, Fuchs R, CLUSTAL V: improved software for multiple sequence alignment.Comput Appl Biosci. 1992;8:189–191.PubMedGoogle Scholar
  54. 54.
    Thompson JD, Higgins DG, Gibson TJ, CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.Nucleic Acids Res. 1994;22:4673–4680.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Schulze-Gahmen U, Brandsen J, Jones HD, et al. Multiple modes of ligand recognition: crystal structures of cyclin-dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine.Proteins. 1995;22:378–391.PubMedCrossRefGoogle Scholar
  56. 56.
    Wu SY, McNae I, Kontopidis G, et al. Discovery of a novel family of Cdk inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop.Structure. 2003;11:399–410.PubMedCrossRefGoogle Scholar
  57. 57.
    Brown NR, Noble ME, Lawrie AM, et al. Effects of phosphorylation of threonine 160 on cyclin-dependent kinase 2 structure and activity.J Biol Chem. 1999;274:8746–8756.PubMedCrossRefGoogle Scholar
  58. 58.
    Schulze-Gahmen U, De Bondt HL, Kim SH. High-resolution crystal structures of human cyclin-dependent kinase 2 with and without ATP: bound waters and natural ligand as guides for inhibitor design.J Med Chem. 1996;39:4540–4546.PubMedCrossRefGoogle Scholar
  59. 59.
    Card GL, Knowles P, Laman H, et al. Crystal structure of a gamma-herpesvirus cyclin-cdk complex.EMBO J. 2000;19:2877–2888.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Russo AA, Jeffrey PD, Pavletich NP. Structural basis of cyclin-dependent kinase activation by phosphorylation.Nat Struct Biol. 1996;3:696–700.PubMedCrossRefGoogle Scholar
  61. 61.
    Jeffrey PD, Russo AA, Polyak K, et al. Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex.Nature. 1995;376:313–320.PubMedCrossRefGoogle Scholar
  62. 62.
    Hardcastle IR, Arris CE, Bentley J, et al. N2-substituted O6-cyclohexylmethylguanine derivatives: potent inhibitors of cyclin-dependent kinases 1 and 2.J Med Chem. 2004;47:3710–3722.PubMedCrossRefGoogle Scholar
  63. 63.
    Sayle KL, Bentley J, Boyle FT, et al. Structure-based design of 2-arylamino-4-cyclohexyl methyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.Bioorg Med Chem Lett. 2003;13:3079–3082.PubMedCrossRefGoogle Scholar
  64. 64.
    Johnson LN, De Moliner E, Brown NR, et al. Structural studies with inhibitors of the cell cycle regulatory kinase cyclin-dependent protein kinase 2.Pharmacol Ther. 2002;93:113–124.PubMedCrossRefGoogle Scholar
  65. 65.
    Davis ST, Benson BG, Bramson HN, et al. Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.Science. 2001;291:134–137.PubMedCrossRefGoogle Scholar
  66. 66.
    Davies TG, Tunnah P, Meijer L, et al. Inhibitor binding to active and inactive cdk2: the crystal structure of cdk2-cyclin A/indirubin-5-sulphonate.Structure. 2001;9:389–397.PubMedCrossRefGoogle Scholar
  67. 67.
    Lawrie AM, Noble ME, Tunnah P, et al. Protein kinase inhibition by staurosporine revealed in details of the molecular interaction with CDK2.Nat Struct Biol. 1997;4:796–801.PubMedCrossRefGoogle Scholar
  68. 68.
    Gray NS, Wodicka L, Thunnissen AM, et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors.Science. 1998;281:533–538.PubMedCrossRefGoogle Scholar
  69. 69.
    Shewchuk L, Hassell A, Wisely B, et al. Binding mode of the 4-anilinoquinazoline class of protein kinase inhibitor: X-ray crystallographic studies of 4-anilinoquinazolines bound to cyclin-dependent kinase 2 and P38 kinase.J Med Chem. 2000;43:133–138.PubMedCrossRefGoogle Scholar
  70. 70.
    Meijer L, Thunissen AM, White AW, et al. Inhibition of cyclin-dependent kinases, gsk-3beta and ck1 by hymenialdisine, a marine sponge constituent.Chem Biol. 2000;7:51–63.PubMedCrossRefGoogle Scholar
  71. 71.
    Arris CE, Boyle FT, Calvert AH, et al. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.J Med Chem. 2000;43:2797–2804.PubMedCrossRefGoogle Scholar
  72. 72.
    Dreyer MK, Borcherding DR, Dumont JA, et al. Crystal structure of human cyclin-dependent kinase 2 in complex with the adenine-derived inhibitor H717.J Med Chem. 2001;44:524–530.PubMedCrossRefGoogle Scholar
  73. 73.
    Ikuta M, Kamata K, Fukasawa K, et al. Crystallographic approach to identification of cyclin-dependent kinase 4 (cdk4)-specific inhibitors by using cdk4 mimic cdk2 protein.J Biol Chem. 2001;276:27548–27554.PubMedCrossRefGoogle Scholar
  74. 74.
    Gibson AE, Arris CE, Bentley J, et al. Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives.J Med Chem. 2002;45:3381–3393.PubMedCrossRefGoogle Scholar
  75. 75.
    Beattie JF, Breault GA, Ellston RPA, et al. Cyclin-dependent kinase 4 inhibitors as a treatment for cancer. Part 1: identification and optimization of substituted 4,6-Bis anilino pyrimidines.Bioorg Med Chem Lett. 2003;13:2955–2960.PubMedCrossRefGoogle Scholar
  76. 76.
    Davies TG, Bentley J, Arris CE, et al. Structure-based design of a potent purine-based cyclin-dependent kinase inhibitor.Nat Struct Biol. 2002;9:745–749.PubMedCrossRefGoogle Scholar
  77. 77.
    Bramson HN, Corona J, Davis ST, et al. Oxindole-based inhibitors of cyclin-dependent kinase 2 (Cdk2): design, synthesis, enzymatic activities, and x-ray crystallographic analysis.J Med Chem. 2001;44:4339–4358.PubMedCrossRefGoogle Scholar
  78. 78.
    Anderson M, Beattie J, Breault G, et al. Imidazo[1,2-A]pyridines: a potent and selective class of cyclin-dependent kinase inhibitors identified through structure-based hydridization.Bioorg Med Chem Lett. 2003;13:3021–3026.PubMedCrossRefGoogle Scholar
  79. 79.
    Liu JJ, Dermatakis A, Lukacs CM, et al. 3,5,6-Trisubstituted naphtostyrils as Cdk2 inhibitors.Bioorg Med Chem Lett. 2003;13:2465–2468.PubMedCrossRefGoogle Scholar
  80. 80.
    Moshinsky DJ, Bellamacina CR, Boisvert DC, et al. Su9516: biochemical analysis of Cdk inhibition and crystal structure in complex with Cdk2.Biochem Biophys Res Commun. 2003;310:1026–1031.PubMedCrossRefGoogle Scholar
  81. 81.
    Wang S, Meades C, Wood G, et al. 2-Anilino-4-(thiazol-5-Yl)pyrimidine Cdk inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.J Med Chem. 2004;47:1662–1675.PubMedCrossRefGoogle Scholar
  82. 82.
    Hamdouchi C, Keyser H, Collins E, et al. The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo.Mol Cancer Ther. 2004;3:1–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Luk K-C, Simcox ME, Schutt A, et al. A new series of potent oxindole inhibitors of cdk2.Bioorg Med Chem Lett. 2004;14:913–917.PubMedCrossRefGoogle Scholar
  84. 84.
    Byth K, Cooper N, Culshaw J, et al. Imidazo[1,2-B]pyridazines: a potent and selective class of cyclin-dependent kinase inhibitors.Bioorg Med Chem Lett. 2004;14:2249–2252.PubMedCrossRefGoogle Scholar
  85. 85.
    Russo AA, Jeffrey PD, Patten AK, et al. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex.Nature. 1996;382:325–331.PubMedCrossRefGoogle Scholar
  86. 86.
    Brown NR, Noble ME, Endicott JA, et al. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases.Nat Cell Biol. 1999;1:438–443.PubMedCrossRefGoogle Scholar
  87. 87.
    Cook A, Lowe ED, Chrysina ED, et al. Structural studies on phospho-Cdk2/cyclin A bound to nitrate, a transition state analogue: implications for the protein kinase mechanism.Biochemistry. 2002;41:7301–7311.PubMedCrossRefGoogle Scholar
  88. 88.
    Mapelli M, Massimiliano L, Crovace C, et al. Mechanism of Cdk5/P25 binding by Cdk inhibitors.J Med Chem. 2005;48:671–679.PubMedCrossRefGoogle Scholar
  89. 89.
    Tarricone C, Dhavan R, Peng J, et al. Structure and regulation of the Cdk5-P25(Nck5A) complex.Mol Cell. 2001;8:657–669.PubMedCrossRefGoogle Scholar
  90. 90.
    Schulze-Gahmen U, Kim SH. Structural basis for Cdk6 activation by a virus-encoded cyclin.Nat Struct Biol. 2002;9:177–181.PubMedGoogle Scholar
  91. 91.
    Russo AA, Tong L, Lee JO, et al. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumor suppressor p16INK4a.Nature. 1998;395:237–243.PubMedCrossRefGoogle Scholar
  92. 92.
    Brotherton DH, Dhanaraj V, Wick S, et al. Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d.Nature. 1998;395:244–250.PubMedCrossRefGoogle Scholar
  93. 93.
    Lu H, Chang DJ, Baratte B, et al. Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin.J Med Chem. 2005;48:737–743.PubMedCrossRefGoogle Scholar
  94. 94.
    Jeffrey PD, Tong L, Pavletich NP. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors.Genes Dev. 2000;14:3115–3125.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Lolli G, Lowe ED, Brown NR, et al. The crystal structure of human cdk7 and its protein recognition properties.Structure. 2004;12:2067–2079.PubMedCrossRefGoogle Scholar
  96. 96.
    Kim KK, Chamberlin HM, Morgan DO, et al. Three-dimensional structure of human cyclin H, a positive regulator of the CDK-activating kinase.Nat Struct Biol. 1996;3:849–855.PubMedCrossRefGoogle Scholar
  97. 97.
    Schulze-Gahmen U, Jung JU, Kim SH. Crystal structure of a viral cyclin, a positive regulator of cyclin-dependent kinase 6.Structure. 1999;7:245–254.PubMedCrossRefGoogle Scholar
  98. 98.
    Venkataramani R, Swaminathan K, Marmorstein R. Crystal structure of the CDK4/6 inhibitory protein p18INK4c provides insights into ankyrin-like repeat structure/function and tumor-derived p16INK4 mutations.Nat Struct Biol. 1998;5:74–81.PubMedCrossRefGoogle Scholar
  99. 99.
    Venkataramani RN, Maclachlan TK, Chai X, et al. Structure-based design of P18Ink4C proteins with increased thermodynamic stability and cell cycle inhibitory activity.J Biol Chem. 2002;277: 48827–48833.PubMedCrossRefGoogle Scholar
  100. 100.
    Li J, Byeon I-J, Ericson K, et al. Tumor suppressor Ink4: determination of the solution structure of P18Ink4C and demonstration of the functional significance of loops in P18Ink4C and P16Ink4A.Biochemistry. 1999;38:2930–2940.PubMedCrossRefGoogle Scholar
  101. 101.
    Byeon IJ, Li J, Ericson K, et al. Tumor suppressor P16Ink4A: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4Mol Cell. 1998;1:421–431.PubMedCrossRefGoogle Scholar
  102. 102.
    Luh FY, Archer SJ, Donnaille PJ, et al. Structure of the cyclin-dependent kinase inhibitor p19Ink4d.Nature. 1997;389:999–1003.PubMedCrossRefGoogle Scholar
  103. 103.
    Yuan C, Li J, Selby TL, et al. Tumor suppressor Ink4: comparisons of conformational properties between P16Ink4A and P18Ink4C.J Mol Biol. 1999;294:201–211.PubMedCrossRefGoogle Scholar
  104. 104.
    Yuan C, Selby TL, Li J, et al. Tumor suppressor Ink4: refinement of P16Ink4A structure and determination of P15Ink4B structure by comparative modeling and NMR data.Protein Sci. 2000;9:1120–1128.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Holton S, Merckx A, Burgess D, et al. Structures of P falciparum PfPK5 test the CDK regulation paradigm and suggest mechanism of small molecule inhibition.Structure. 2003;11:1329–1337.PubMedCrossRefGoogle Scholar
  106. 106.
    Kontopidis G, Andrews M, McInnes C, et al. Insights into cyclin groove recognition: complex crystal structures and inhibitor design through ligand exchange.Structure. 2003;11:1537–1546.PubMedCrossRefGoogle Scholar
  107. 107.
    Andrews M, McInnes C, Kontopodis G, et al. Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes.Org Biomol Chem 2004;2:2735–2741.PubMedCrossRefGoogle Scholar
  108. 108.
    Lowe E, Tews I, Cheng KY, et al. Specificity determinants of recruitment peptides bound to phospho-Cdk2/Cyclin A.Biochemistry. 2002;41:15625–15634.PubMedCrossRefGoogle Scholar
  109. 109.
    Song H, Hanlon N, Brown NR, et al. Phosphoprotein-protein interactiosn revealed by the crystal structure of kinase-associated phosphatase in complex with phospho-CDK2.Mol Cell. 2001;7:615–626.PubMedCrossRefGoogle Scholar
  110. 110.
    MAG.GeneMine/Look. Palo Alto, CA: e.M.A.G; 1999.Google Scholar
  111. 111.
    MAG.GeneMine/Look, 3.5.2ed. Palo Alto, CA: Molecular Application Group; 1999.Google Scholar
  112. 112.
    McGrath CF, Pattabiraman N, Kellogg GE, et al. Homology model of the CDK1/cyclin B complex.J Biomol Struct Dyn. 2005;22:493–502.PubMedCrossRefGoogle Scholar
  113. 113.
    Gussio R, Zaharewitz DW, McGrath CF, et al. Structure-based design modifications of the paullone molecular scaffold for cyclin-dependent kinase inhibition.Anticancer Drug Des. 2000;15:53–66.PubMedGoogle Scholar
  114. 114.
    Heiden W, Moeckel G, Brickmann J. A new approach to analysis and display of local lipophilicity/hydrophilicity mapped on molecular surfaces.J Comput Aided Mol Des. 1993;7:503–514.PubMedCrossRefGoogle Scholar
  115. 115.
    Vesely J, Havlicek L, Strnad M, et al. Inhibition of cyclin-dependent kinases by purine analogues.Eur J Biochem. 1994;224:771–786.PubMedCrossRefGoogle Scholar
  116. 116.
    De Azevedo WF, Leclerc S, Meijer L, et al. Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human CDK2 complexed with roscovitine.Eur J Biochem. 1997;243:518–526.PubMedCrossRefGoogle Scholar
  117. 117.
    Ongkeko W, Ferguson DJ, Harris AL, et al. Inactivation of CDC2 increases the level of apoptosis induced by DNA damage.J Cell Sci. 1995;108:2897–2904.PubMedGoogle Scholar
  118. 118.
    Glab N, Labidi B, Qin LX, et al. Olomoucine, an inhibitor of the CDC2/CDK2 kinases activity, blocks plant cells at the G1 to S and G2 to M cell cycle transitions.FEBS Lett. 1994;353:207–211.PubMedCrossRefGoogle Scholar
  119. 119.
    Meijer L. Chemical inhibitors of cyclin-dependent kinases.Trends Cell Biol. 1996;6:393–397.PubMedCrossRefGoogle Scholar
  120. 120.
    Gadbois D, Hamaguchi JR, Swank RA, et al. Staurosporine is a potent inhibitor of p34cdc2 and p34cdc2-like kinases.Biochem Biophys Res Commun. 1992;184:80–85.PubMedCrossRefGoogle Scholar
  121. 121.
    Pereira ER, Belin L, Sancelme M, et al. Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties.J Med Chem. 1996;39:4471–4477.PubMedCrossRefGoogle Scholar
  122. 122.
    Wood L, Stoltz BM, Goodman SN. Total synthesis of (+)-RK-286c, (+)-MLR-52, (+)-staurosporine, and (+)-K252a.J Am Chem Soc. 1996;118:10656–10657.CrossRefGoogle Scholar
  123. 123.
    Sedlacek HH, Czech J, Nai KR, et al. Flavopiridol (L86 8275; NSC 649890), a new kinase inhibitor for tumor therapy.Int J Oncol. 1996;9:1143–1168.PubMedGoogle Scholar
  124. 124.
    Carlson BA, Dubay MM, Sausville EA, et al. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase CDK2 and CDK4 in human breast carcinoma cells.Cancer Res. 1996;56:2973–2978.PubMedGoogle Scholar
  125. 125.
    Arris CE, Boyle FT, Calvert AH, et al. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles.J Med Chem. 2000;43:2797–2804.PubMedCrossRefGoogle Scholar
  126. 126.
    Boschelli DH, Bdobrusin EM, Doherty AM, et al, inventors. Warner Lambert Co., assignee. Preparation of pyrido[2,3-d]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation. Patent WO9833798. August 6, 1998.Google Scholar
  127. 127.
    Soni R, O'Reilly T, Furet P, et al. Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4.J Natl Cancer Inst. 2001;93:436–446.PubMedCrossRefGoogle Scholar
  128. 128.
    Kent LL, Hull-Campbell NE, Lau T, et al. Characterization of novel inhibitors of cyclin-dependent kinases.Biochem Biophys Res Commun. 1999;260:768–774.PubMedCrossRefGoogle Scholar
  129. 129.
    Bramson HN, Corona J, Davis ST, et al. Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2) design, synthesis enzymatic activities.J Med Chem. 2004;44:4339–4358.CrossRefGoogle Scholar
  130. 130.
    Zaharevitz DW, Gussio R, Leost M, et al. Discovery and initial characterization of the paullones, a novel class of small-molecule inhibitors of cyclin-dependent kinases.Cancer Res. 1999;59:2566–2569.PubMedGoogle Scholar
  131. 131.
    Schultz C, Link A, Leost M, et al. 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.PubMedCrossRefGoogle Scholar
  132. 132.
    Honma T, Hayashi K, Aoyama T, et al. Structure-based generation of a new class of potent Cdk4 inhibitors: new de novo design strategy and library design.J Med Chem. 2001;44:4615–4627.PubMedCrossRefGoogle Scholar
  133. 133.
    Vesely J, Havlicek L, Strnad M, et al. Inhibition of cyclin-dependent kinases by purine analogues.Eur J Biochem. 1994;224:771–786.PubMedCrossRefGoogle Scholar
  134. 134.
    Kim KS, Sack JS, Tokarski JS, et al. Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective inhibitors: synthesis and biological effects.J Med Chem. 2000;43:4126–4134.PubMedCrossRefGoogle Scholar
  135. 135.
    Bramson HN, Corona J, Davis ST, et al. Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.J Med Chem. 2001;44:4339–4358.PubMedCrossRefGoogle Scholar
  136. 136.
    Sielecki TM, Johnson TL, Liu J, et al. Quinazolines as cyclin-dependent kinase inhibitors.Bioorg Med Chem Lett. 2001;11:1157–1160.PubMedCrossRefGoogle Scholar
  137. 137.
    Furet P, Meyer T, Strauss A, et al. Structure-based design and protein X-ray analysis of a protein kinase inhibitor.Bioorg Med Chem Lett. 2002;12:221–224.PubMedCrossRefGoogle Scholar
  138. 138.
    Misra RN, Xiao H, Rawlins DB, et al. 1H-Pyrazolo[3,4-b]pyridine inhibitors of cyclin-dependent kinases: highly potent 2, 6-difluorophenacyl analogues.Bioorg Med Chem Lett. 2003;13:2405–2408.PubMedCrossRefGoogle Scholar
  139. 139.
    Mesguiche V, Parsons RJ, Arris CE, et al. 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin-dependent kinases 1 and 2.Bioorg Med Chem Lett. 2003;13:217–222.PubMedCrossRefGoogle Scholar
  140. 140.
    Sayle KL, Bentley J, Boyle FT, et al. Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.Bioorg Med Chem Lett. 2003;13:3079–3082.PubMedCrossRefGoogle Scholar
  141. 141.
    Jaramillo C, de Diego JE, Hamdouchi C, et al. Aminoimidazo[1,2-a]pyridines as a new structural class of cyclin-dependent kinase inhibitors. Part 1: design, synthesis, and biological evaluation.Bioorg Med Chem Lett. 2004;14:6095–6099.PubMedCrossRefGoogle Scholar
  142. 142.
    Helal CJ, Sanner MA, Cooper CB, et al. Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer's disease.Bioorg Med Chem Lett. 2004;14:5521–5525.PubMedCrossRefGoogle Scholar
  143. 143.
    Nugiel DA, Vidwans A, Dzierba CD. Parallel synthesis of acylsemicarbazide libraries: preparation of potent cyclin-dependent kinase (cdk) inhibitors.Bioorg Med Chem Lett. 2004;14:5489–5491.PubMedCrossRefGoogle Scholar
  144. 144.
    Pevarello P, Brasca MG, Amici R, et al. 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents, I: lead finding.J Med Chem. 2004;47:3367–3380.PubMedCrossRefGoogle Scholar
  145. 145.
    Hamdouchi C, Zhong B, Mendoza J, et al. Structure-based design of a new class of highly selective aminoimidazo[1,2-a]pyridine-based inhibitors of cyclin-dependent kinases.Bioorg Med Chem Lett. 2005;15:1943–1947.PubMedCrossRefGoogle Scholar
  146. 146.
    Sondhi SM, Goyal RN, Lahoti AM, et al. Synthesis and biological evaluation of 2-thiopyrimidine derivatives.Bioorg Med Chem. 2005;13:3185–3195.PubMedCrossRefGoogle Scholar
  147. 147.
    Verma S, Nagarathanm D, Shao J, et al. Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors.Bioorg Med Chem Lett. 2005;15:1973–1977.PubMedCrossRefGoogle Scholar
  148. 148.
    Senderowicz AM. Small molecule modulators of cyclin-dependent kinases for cancer therapy.Oncogene. 2000;19:6600–6606.PubMedCrossRefGoogle Scholar
  149. 149.
    Huwe A, Mazitschek R, Giannis A. Small molecules as inhibitors of cyclin-dependent kinases.Angew Chem Int Ed Engl. 2003;42:2122–2138.PubMedCrossRefGoogle Scholar
  150. 150.
    Pattabiraman N. Occluded molecular surface analysis of ligandmacromolecule contacts: application to HIV-1 protease-inhibitor complexes.J Med Chem. 1999;42:3821–3834.PubMedCrossRefGoogle Scholar
  151. 151.
    Pattabiraman N. Analysis of ligand-macromolecule contacts: computational methods.Curr Med Chem. 2002;9:609–621.PubMedCrossRefGoogle Scholar
  152. 152.
    Wang C, Li Z, Fu M, et al. Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential.Cancer Treat Res. 2004;119:217–237.PubMedCrossRefGoogle Scholar
  153. 153.
    Payton M, Coats S. Cyclin E2, the cycle continues.Int J Biochem Cell Biol. 2002;34:315–320.PubMedCrossRefGoogle Scholar
  154. 154.
    Hanahan D, Weinberg RA. The hallmarks of cancer.Cell. 2000;100:57–70.PubMedCrossRefGoogle Scholar
  155. 155.
    Morgan DO. Principles of CDK regulation.Nature. 1995;374:131–134.PubMedCrossRefGoogle Scholar
  156. 156.
    Benzeno S, Narla G, Allina J, et al. Cyclin-dependent kinase inhibition by the KLF6 tumor suppressor protein through interaction with cyclin D1.Cancer Res. 2004;64:3885–3891.PubMedCrossRefGoogle Scholar
  157. 157.
    Hu X, Bryington M, Fisher AB, et al. Ubiquitin/proteasome-dependent degradation of D-type cyclins is linked to tumor necrosis factor-induced cell cycle arrest.J Biol Chem. 2002;277:16528–16537.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  • Jayalakshmi Sridhar
    • 1
  • Nagaraju Akula
    • 1
  • Nagarajan Pattabiraman
    • 1
    • 2
    Email author
  1. 1.Laboratory for In-silico Biology and Drug Discovery, Department of Oncology, Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashington, DC
  2. 2.Department of Biochemistry & Molecular BiologyGeorgetown UniversityWashington DC

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