Cyclin-dependent kinase inhibitors as anticancer therapeutics

Molecular Pharmacology

Volumn 88, Issue 5, 2015, Pages 846-852

  Law, Mary E ^a,b   Corsino, Patrick E ^a,b   Narayan, Satya ^a,b   Law, Brian K ^a,b  

^a UNIVERSITY OF FLORIDA   (United States)

^b UNIVERSITY OF FLORIDA HEALTH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (2 CHLOROPHENYL) 5,7 DIHYDROXY 8 [2 (HYDROXYMETHYL) 1 METHYLPYRROLIDIN 3 YL]CHROMEN 4 ONE; 4 [(2,6 DICHLOROBENZOYL)AMINO] N PIPERIDIN 4 YL 1H PYRAZOLE 5 CARBOXAMIDE METHANESULFONIC ACID; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 5; CYCLIN DEPENDENT KINASE 6; CYCLIN DEPENDENT KINASE 7; CYCLIN DEPENDENT KINASE 8; CYCLIN DEPENDENT KINASE 9; CYCLIN DEPENDENT KINASE INHIBITOR; DINACICLIB; N [5 (5 TERT BUTYL 2 OXAZOLYLMETHYLTHIO) 2 THIAZOLYL]ISONIPECOTAMIDE; N [[5 [3 (4,6 DIFLUOROBENZIMIDAZOL 2 YLIDENE) 1,2 DIHYDROINDAZOL 5 YL] 4 METHYLPYRIDIN 3 YL]METHYL]ETHANAMINE; PALBOCICLIB; RONICICLIB; UNCLASSIFIED DRUG; VORUCICLIB; ANTINEOPLASTIC AGENT; CYCLIN DEPENDENT KINASE; FUSED HETEROCYCLIC RINGS; PIPERAZINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PYRIDINE DERIVATIVE; PYRIDINIUM DERIVATIVE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; BINDING SITE; BREAST CANCER; CELL CYCLE; CELL DEATH; CELL PROLIFERATION; CHROMOSOMAL INSTABILITY; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL TRIAL (TOPIC); CRYSTAL STRUCTURE; DRUG MECHANISM; DRUG TARGETING; ENZYME INHIBITION; FOOD AND DRUG ADMINISTRATION; HUMAN; NONHUMAN; PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG DEVELOPMENT; DRUG EFFECTS;

ANIMALS; ANTINEOPLASTIC AGENTS; BRIDGED BICYCLO COMPOUNDS, HETEROCYCLIC; CELL CYCLE; CHROMOSOMAL INSTABILITY; CYCLIN-DEPENDENT KINASES; DRUG DISCOVERY; HUMANS; PIPERAZINES; PROTEIN KINASE INHIBITORS; PYRIDINES; PYRIDINIUM COMPOUNDS;

EID: 84946550419     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.115.099325     Document Type: Article

References (109)

1. Adhikari D, Zheng W, Shen Y, Gorre N, Ning Y, Halet G, Kaldis P, and Liu K (2012) Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. Hum Mol Genet 21:2476-2484.
2. Adon AM, Zeng X, Harrison MK, Sannem S, Kiyokawa H, Kaldis P, and Saavedra HI (2010) Cdk2 and Cdk4 regulate the centrosome cycle and are critical mediators of centrosome amplification in p53-null cells. Mol Cell Biol 30:694-710.
3. Akiyama T, Ohuchi T, Sumida S, Matsumoto K, and Toyoshima K (1992) Phosphorylation of the retinoblastoma protein by cdk2. Proc Natl Acad Sci USA 89: 7900-7904.
4. Akli S, Zheng PJ, Multani AS, Wingate HF, Pathak S, Zhang N, Tucker SL, Chang S, and Keyomarsi K (2004) Tumor-specific low molecular weight forms of cyclin E induce genomic instability and resistance to p21, p27, and antiestrogens in breast cancer. Cancer Res 64:3198-3208.
5. Allen BL and Taatjes DJ (2015) The Mediator complex: A central integrator of transcription. Nat Rev Mol Cell Biol 16:155-166.
6. Andrews MJ, Kontopidis G, McInnes C, Plater A, Innes L, Cowan A, Jewsbury P, and Fischer PM (2006) REPLACE: A strategy for iterative design of cyclin-binding groove inhibitors. Chem Bio Chem 7:1909-1915.
7. Andrews MJ, McInnes C, Kontopidis G, Innes L, Cowan A, Plater A, and Fischer PM (2004) Design, synthesis, biological activity and structural analysis of cyclic peptide inhibitors targeting the substrate recruitment site of cyclin-dependent kinase complexes. Org Biomol Chem 2:2735-2741.
8. Barrière C, Santamaría D, Cerqueira A, Galán J, Martín A, Ortega S, Malumbres M, Dubus P, and Barbacid M (2007) Mice thrive without Cdk4 and Cdk2. Mol Oncol 1: 72-83.
9. Berthet C, Aleem E, Coppola V, Tessarollo L, and Kaldis P (2003) Cdk2 knockout mice are viable. Curr Biol 13:1775-1785.
10. Berthet C and Kaldis P (2006) Cdk2 and Cdk4 cooperatively control the expression of Cdc2. Cell Div 1:10.
11. Bienvenu F, Jirawatnotai S, Elias JE, Meyer CA, Mizeracka K, Marson A, Frampton GM, Cole MF, Odom DT, and Odajima J et al. (2010) Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen. Nature 463:374-378.
12. Bishop AC, Ubersax JA, Petsch DT, Matheos DP, Gray NS, Blethrow J, Shimizu E, Tsien JZ, Schultz PG, and Rose MD et al. (2000) A chemical switch for inhibitorsensitive alleles of any protein kinase. Nature 407:395-401.
13. Blachly JS and Byrd JC (2013) Emerging drug profile: cyclin-dependent kinase inhibitors. Leuk Lymphoma 54:2133-2143.
14. Blagosklonny MV (2004) Flavopiridol, an inhibitor of transcription: implications, problems and solutions. Cell Cycle 3:1537-1542.
15. Brown NR, Noble ME, Endicott JA, and Johnson LN (1999) The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nat Cell Biol 1:438-443.
16. Cánepa ET, Scassa ME, Ceruti JM, Marazita MC, Carcagno AL, Sirkin PF, and Ogara MF (2007) INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 59:419-426.
17. Cao K and Shilatifard A (2014) Inhibit globally, act locally: CDK7 inhibitors in cancer therapy. Cancer Cell 26:158-159.
18. Chellappan SP, Hiebert S, Mudryj M, Horowitz JM, and Nevins JR (1991) The E2F transcription factor is a cellular target for the RB protein. Cell 65:1053-1061.
19. Cheng CK, Gustafson WC, Charron E, Houseman BT, Zunder E, Goga A, Gray NS, Pollok B, Oakes SA, and James CD et al. (2012) Dual blockade of lipid and cyclindependent kinases induces synthetic lethality in malignant glioma. Proc Natl Acad Sci USA 109:12722-12727.
20. Chipumuro E, Marco E, Christensen CL, Kwiatkowski N, Zhang T, Hatheway CM, Abraham BJ, Sharma B, Yeung C, and Altabef A et al. (2014) CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell 159:1126-1139.
21. Christensen CL, Kwiatkowski N, Abraham BJ, Carretero J, Al-Shahrour F, Zhang T, Chipumuro E, Herter-Sprie GS, Akbay EA, and Altabef A et al. (2014) Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26:909-922.
22. Christian BA, Grever MR, Byrd JC, and Lin TS (2007) Flavopiridol in the treatment of chronic lymphocytic leukemia. Curr Opin Oncol 19:573-578.
23. Cobrinik D, Dowdy SF, Hinds PW, Mittnacht S, and Weinberg RA (1992) The retinoblastoma protein and the regulation of cell cycling. Trends Biochem Sci 17: 312-315.
24. Corsino P, Davis B, Law M, Chytil A, Forrester E, Nørgaard P, Teoh N, and Law B (2007) Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression. Cancer Res 67:3135-3144.
25. Corsino P, Horenstein N, Ostrov D, Rowe T, Law M, Barrett A, Aslanidi G, Cress WD, and Law B (2009) A novel class of cyclin-dependent kinase inhibitors identified by molecular docking act through a unique mechanism. J Biol Chem 284: 29945-29955.
26. Corsino PE, Davis BJ, Nørgaard PH, Parker NN, Law M, Dunn W, and Law BK (2008) Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component. Neoplasia 10:1240-1252.
27. De Azevedo WF, Leclerc S, Meijer L, Havlicek L, Strnad M, and Kim SH (1997) Inhibition of cyclin-dependent kinases by purine analogues: crystal structure of human cdk2 complexed with roscovitine. Eur J Biochem 243:518-526.
28. De Falco G and Giordano A (2002) CDK9: from basal transcription to cancer and AIDS. Cancer Biol Ther 1:342-347.
29. Demelash A, Rudrabhatla P, Pant HC, Wang X, Amin ND, McWhite CD, Naizhen X, and Linnoila RI (2012) Achaete-scute homologue-1 (ASH1) stimulates migration of lung cancer cells through Cdk5/p35 pathway. Mol Biol Cell 23:2856-2866.
30. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, Lal P, Feldman M, Zhang P, and Colameco C et al. (2015) CDK 4/6 inhibitor palbociclib (PD0332991) in Rb1 advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res 21:995-1001.
31. Deng Y, Shipps GW Jr, Zhao L, Siddiqui MA, Popovici-Muller J, Curran PJ, Duca JS, Hruza AW, Fischmann TO, and Madison VS et al. (2014) Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor. Bioorg Med Chem Lett 24:199-203.
32. Dickson MA, Tap WD, Keohan ML, D'Angelo SP, Gounder MM, Antonescu CR, Landa J, Qin LX, Rathbone DD, and Condy MM et al. (2013) Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified welldifferentiated or dedifferentiated liposarcoma. J Clin Oncol 31:2024-2028.
33. Diril MK, Ratnacaram CK, Padmakumar VC, Du T, Wasser M, Coppola V, Tessarollo L, and Kaldis P (2012) Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration. Proc Natl Acad Sci USA 109:3826-3831.
34. Duensing A, Liu Y, Tseng M, Malumbres M, Barbacid M, and Duensing S (2006) Cyclin-dependent kinase 2 is dispensable for normal centrosome duplication but required for oncogene-induced centrosome overduplication. Oncogene 25: 2943-2949.
35. el-Deiry WS, Harper JW, O'Connor PM, Velculescu VE, Canman CE, Jackman J, Pietenpol JA, Burrell M, Hill DE, and Wang Y et al. (1994) WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 54:1169-1174.
36. Elphick LM, Lee SE, Child ES, Prasad A, Pignocchi C, Thibaudeau S, Anderson AA, Bonnac L, Gouverneur V, and Mann DJ (2009) A quantitative comparison of wildtype and gatekeeper mutant cdk2 for chemical genetic studies with ATP analogues. Chem Bio Chem 10:1519-1526.
37. Enserink JM, Hombauer H, Huang ME, and Kolodner RD (2009) Cdc28/Cdk1 positively and negatively affects genome stability in S. cerevisiae. J Cell Biol 185: 423-437.
38. Etemadmoghadam D, Weir BA, Au-Yeung G, Alsop K, Mitchell G, George J, Davis S, D'Andrea AD, Simpson K, and Hahn WC et al.; Australian Ovarian Cancer Study Group (2013) Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc Natl Acad Sci USA 110:19489-19494.
39. Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, Goggins M, Maitra A, and Nelkin BD (2010) Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res 70:4460-4469.
40. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, and Schmidt M et al. (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 16: 25-35.
41. Firestein R, Bass AJ, Kim SY, Dunn IF, Silver SJ, Guney I, Freed E, Ligon AH, Vena N, and Ogino S et al. (2008) CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity. Nature 455:547-551.
42. Fisher RP (2005) Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 118:5171-5180.
43. Flynn J, Jones J, Johnson AJ, Andritsos L, Maddocks K, Jaglowski S, Hessler J, Grever MR, Im E, and Zhou H et al. (2015) Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia DOI:10.1038/leu.2015.31 [published ahead of print].
44. Galons H, Oumata N, Gloulou O, and Meijer L (2013) Cyclin-dependent kinase inhibitors closer to market launch? Expert Opin Ther Pat 23:945-963.
45. Goodyear S and Sharma MC (2007) Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol 82:25-32.
46. Gravells P, Tomita K, Booth A, Poznansky J, and Porter AC (2013) Chemical genetic analyses of quantitative changes in Cdk1 activity during the human cell cycle. Hum Mol Genet 22:2842-2851.
47. Gu W, Wang C, Li W, Hsu FN, Tian L, Zhou J, Yuan C, Xie XJ, Jiang T, and Addya S et al. (2013) Tumor-suppressive effects of CDK8 in endometrial cancer cells. Cell Cycle 12:987-999.
48. He L, Lu N, Dai Q, Zhao Y, Zhao L, Wang H, Li Z, You Q, and Guo Q (2013) Wogonin induced G1 cell cycle arrest by regulating Wnt/b-catenin signaling pathway and inactivating CDK8 in human colorectal cancer carcinoma cells. Toxicology 312: 36-47.
49. Hiebert SW, Chellappan SP, Horowitz JM, and Nevins JR (1992) The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F. Genes Dev 6:177-185.
50. Horiuchi D, Huskey NE, Kusdra L, Wohlbold L, Merrick KA, Zhang C, Creasman KJ, Shokat KM, Fisher RP, and Goga A (2012) Chemical-genetic analysis of cyclin dependent kinase 2 function reveals an important role in cellular transformation by multiple oncogenic pathways. Proc Natl Acad Sci USA 109:E1019-E1027.
51. Hubalek MM, Widschwendter A, Erdel M, Gschwendtner A, Fiegl HM, Müller HM, Goebel G, Mueller-Holzner E, Marth C, and Spruck CH et al. (2004) Cyclin E dysregulation and chromosomal instability in endometrial cancer. Oncogene 23: 4187-4192.
52. Hudis C, Swanton C, Janjigian YY, Lee R, Sutherland S, Lehman R, Chandarlapaty S, Hamilton N, Gajria D, and Knowles J et al. (2013) A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors. Breast Cancer Res 15:R110.
53. Jahn SC, Corsino PE, Davis BJ, Law ME, Nørgaard P, and Law BK (2013a) Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints. J Cell Sci 126:1207-1217.
54. Jahn SC, Law ME, Corsino PE, Rowe TC, Davis BJ, and Law BK (2013b) Assembly, activation, and substrate specificity of cyclin D1/Cdk2 complexes. Biochemistry 52: 3489-3501.
55. Johnson DG, Cress WD, Jakoi L, and Nevins JR (1994) Oncogenic capacity of the E2F1 gene. Proc Natl Acad Sci USA 91:12823-12827.
56. Jorda R, Paruch K, and Krystof V (2012) Cyclin-dependent kinase inhibitors inspired by roscovitine: purine bioisosteres. Curr Pharm Des 18:2974-2980.
57. Kawamura K, Izumi H, Ma Z, Ikeda R, Moriyama M, Tanaka T, Nojima T, Levin LS, Fujikawa-Yamamoto K, and Suzuki K et al. (2004) Induction of centrosome amplification and chromosome instability in human bladder cancer cells by p53 mutation and cyclin E overexpression. Cancer Res 64:4800-4809.
58. Keyomarsi K, Conte D Jr, Toyofuku W, and Fox MP (1995) Deregulation of cyclin E in breast cancer. Oncogene 11:941-950.
59. Keyomarsi K and Pardee AB (1993) Redundant cyclin overexpression and gene amplification in breast cancer cells. Proc Natl Acad Sci USA 90:1112-1116.
60. Kim D, Sun M, He L, Zhou QH, Chen J, Sun XM, Bepler G, Sebti SM, and Cheng JQ (2010) A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation. J Biol Chem 285:8383-8394.
61. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820-823.
62. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, and Tesar B et al. (2014) Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511:616-620.
63. Leonard JP, LaCasce AS, Smith MR, Noy A, Chirieac LR, Rodig SJ, Yu JQ, Vallabhajosula S, Schoder H, and English P et al. (2012) Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119:4597-4607.
64. Li J, Li X, Kong X, Luo Q, Zhang J, and Fang L (2014a) MiRNA-26b inhibits cellular proliferation by targeting CDK8 in breast cancer. Int J Clin Exp Med 7:558-565.
65. Li X, Zhang XA, Li X, Xie W, and Huang S (2015) MYC-mediated synthetic lethality for treating tumors. Curr Cancer Drug Targets 15:99-115.
66. Li XY, Luo QF, Wei CK, Li DF, and Fang L (2014b) siRNA-mediated silencing of CDK8 inhibits proliferation and growth in breast cancer cells. Int J Clin Exp Pathol 7:92-100.
67. Li XY, Luo QF, Wei CK, Li DF, Li J, and Fang L (2014c) MiRNA-107 inhibits proliferation and migration by targeting CDK8 in breast cancer. Int J Clin Exp Med 7: 32-40.
68. Liang Q, Li L, Zhang J, Lei Y, Wang L, Liu DX, Feng J, Hou P, Yao R, and Zhang Y et al. (2013) CDK5 is essential for TGF-b1-induced epithelial-mesenchymal transition and breast cancer progression. Sci Rep 3:2932.
69. Liu X, Shi S, Lam F, Pepper C, Fischer PM, and Wang S (2012) CDKI-71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer cells compared to flavopiridol. Int J Cancer 130:1216-1226.
70. Malumbres M, Sotillo R, Santamaría D, Galán J, Cerezo A, Ortega S, Dubus P, and Barbacid M (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118:493-504.
71. Manning G, Whyte DB, Martinez R, Hunter T, and Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912-1934.
72. Manzo SG, Zhou ZL, Wang YQ, Marinello J, He JX, Li YC, Ding J, Capranico G, and Miao ZH (2012) Natural product triptolide mediates cancer cell death by triggering CDK7-dependent degradation of RNA polymerase II. Cancer Res 72: 5363-5373.
73. Martin MP, AlamR, Betzi S, Ingles DJ, Zhu JY, and Schönbrunn E (2012) A novel approach to the discovery of small-molecule ligands of CDK2. Chem Bio Chem 13:2128-2136.
74. Martin MP, Olesen SH, Georg GI, and Schönbrunn E (2013) Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chem Biol 8:2360-2365.
75. Matsushime H, Ewen ME, Strom DK, Kato JY, Hanks SK, Roussel MF, and Sherr CJ (1992) Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71:323-334.
76. Meijer L and Raymond E (2003) Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res 36:417-425.
77. Michaud K, Solomon DA, Oermann E, Kim JS, Zhong WZ, Prados MD, Ozawa T, James CD, and Waldman T (2010) Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 70:3228-3238.
78. Molenaar JJ, Ebus ME, Geerts D, Koster J, Lamers F, Valentijn LJ, Westerhout EM, Versteeg R, and Caron HN (2009) Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells. Proc Natl Acad Sci USA 106:12968-12973.
79. Nevins JR, Chellappan SP, Mudryj M, Hiebert S, Devoto S, Horowitz J, Hunter T, and Pines J (1991) E2F transcription factor is a target for the RB protein and the cyclin A protein. Cold Spring Harb Symp Quant Biol 56:157-162.
80. Nowicki MW and Walkinshaw MD (2010) CDK9 inhibitors push cancer cells over the edge. Chem Biol 17:1047-1048.
81. Nurse P and Thuriaux P (1980) Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics 96:627-637.
82. Okuda T, Shurtleff SA, Valentine MB, Raimondi SC, Head DR, Behm F, Curcio-Brint AM, Liu Q, Pui CH, and Sherr CJ et al. (1995) Frequent deletion of p16INK4a/MTS1 and p15INK4b/MTS2 in pediatric acute lymphoblastic leukemia. Blood 85: 2321-2330.
83. Ortega S, Prieto I, Odajima J, Martín A, Dubus P, Sotillo R, Barbero JL, Malumbres M, and Barbacid M (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25-31.
84. Pardee AB (1974) A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71:1286-1290.
85. Polier G, Ding J, Konkimalla BV, Eick D, Ribeiro N, Köhler R, Giaisi M, Efferth T, Desaubry L, and Krammer PH et al. (2011) Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1. Cell Death Dis 2:e182.
86. Polier G, Giaisi M, Köhler R, Müller WW, Lutz C, Buss EC, Krammer PH, and Li-Weber M (2015) Targeting CDK9 by wogonin and related natural flavones potentiates the anti-cancer efficacy of the Bcl-2 family inhibitor ABT-263. Int J Cancer 136:688-698.
87. Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V, Meyer D, Guo A, Gundara J, and Mettlach G et al. (2013) The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24:499-511.
88. Rane SG, Cosenza SC, Mettus RV, and Reddy EP (2002) Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol 22:644-656.
89. Ray D, Terao Y, Christov K, Kaldis P, and Kiyokawa H (2011) Cdk2-null mice are resistant to ErbB-2-induced mammary tumorigenesis. Neoplasia 13:439-444.
90. Reddy HK, Mettus RV, Rane SG, Graña X, Litvin J, and Reddy EP (2005) Cyclindependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res 65:10174-10178.
91. Rong JJ, Hu R, Song XM, Ha J, Lu N, Qi Q, Tao L, You QD, and Guo QL (2010) Gambogic acid triggers DNA damage signaling that induces p53/p21(Waf1/CIP1) activation through the ATR-Chk1 pathway. Cancer Lett 296:55-64.
92. Russo AA, Jeffrey PD, Patten AK, Massagué J, and Pavletich NP (1996) Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin ACdk2 complex. Nature 382:325-331.
93. Sheaff RJ, Groudine M, Gordon M, Roberts JM, and Clurman BE (1997) Cyclin ECDK2 is a regulator of p27Kip1. Genes Dev 11:1464-1478.
94. Sherr CJ (1996) Cancer cell cycles. Science 274:1672-1677.
95. Sherr CJ, Matsushime H, and Roussel MF (1992) Regulation of CYL/cyclin D genes by colony-stimulating factor 1. Ciba Found Symp 170:209-219, discussion 219- 226.
96. Shiohara M, el-Deiry WS, Wada M, Nakamaki T, Takeuchi S, Yang R, Chen DL, Vogelstein B, and Koeffler HP (1994) Absence of WAF1 mutations in a variety of human malignancies. Blood 84:3781-3784.
97. Sotillo R, García JF, Ortega S, Martin J, Dubus P, Barbacid M, and Malumbres M (2001) Invasive melanoma in Cdk4-targeted mice. Proc Natl Acad Sci USA 98: 13312-13317.
98. Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Bénard J, and Bressac-de Paillerets B; The French Familial Melanoma Study Group (1998) Prevalence of p16 and CDK4 germline mutations in 48 melanomaprone families in France. Hum Mol Genet 7:209-216.
99. Spirin KS, Simpson JF, Takeuchi S, Kawamata N, Miller CW, and Koeffler HP (1996) p27/Kip1 mutation found in breast cancer. Cancer Res 56:2400-2404.
100. Takeuchi S, Mori N, Koike M, Slater J, Park S, Miller CW, Miyoshi I, and Koeffler HP (1996) Frequent loss of heterozygosity in region of the KIP1 locus in non-small cell lung cancer: evidence for a new tumor suppressor gene on the short arm of chromosome 12. Cancer Res 56:738-740.
101. Tetsu O and McCormick F (2003) Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3:233-245.
102. Viera A, Rufas JS, Martínez I, Barbero JL, Ortega S, and Suja JA (2009) CDK2 is required for proper homologous pairing, recombination and sex-body formation during male mouse meiosis. J Cell Sci 122:2149-2159.
103. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, Lockerman EL, Pollack SF, Liu M, and Li X et al. (2014) CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26:136-149.
104. Wang L, Gao W, Hu F, Xu Z, and Wang F (2014) MicroRNA-874 inhibits cell proliferation and induces apoptosis in human breast cancer by targeting CDK9. FEBS Lett 588:4527-4535.
105. Wang LM and Ren DM (2010) Flavopiridol, the first cyclin-dependent kinase inhibitor: recent advances in combination chemotherapy. Mini Rev Med Chem 10: 1058-1070.
106. Wirger A, Perabo FG, Burgemeister S, Haase L, Schmidt DH, Doehn C, Mueller SC, and Jocham D (2005) Flavopiridol, an inhibitor of cyclin-dependent kinases, induces growth inhibition and apoptosis in bladder cancer cells in vitro and in vivo. Anticancer Res 25 (6B):4341-4347.
107. Xu W, Wang Z, Zhang W, Qian K, Li H, Kong D, Li Y, and Tang Y (2015) Mutated Kras activates CDK8 to stimulate the epithelial-to-mesenchymal transition in pancreatic cancer in part via the Wnt/b-catenin signaling pathway. Cancer Lett 356 (2 Pt B):613-627.
108. Young RJ, Waldeck K, Martin C, Foo JH, Cameron DP, Kirby L, Do H, Mitchell C, Cullinane C, and Liu W et al. (2014) Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res 27: 590-600.
109. Zimmermann C, Chymkowitch P, Eldholm V, Putnam CD, Lindvall JM, Omerzu M, Bjørås M, Kolodner RD, and Enserink JM (2011) A chemical-genetic screen to unravel the genetic network of CDC28/CDK1 links ubiquitin and Rad6-Bre1 to cell cycle progression. Proc Natl Acad Sci USA 108:18748-18753.