Advanced search
Publication Cover
Expert Opinion on Drug Discovery Volume 3, 2008 - Issue 1
Submit an article Journal homepage
149
Views
16
CrossRef citations to date
0
Altmetric
Case History

Seliciclib, a cell-cycle modulator that acts through the inhibition of cyclin-dependent kinases

Robert C Jackson Pharmacometrics Ltd, 51 North Road, Whittlesford, Cambridge CB22 4NZ, UK +44 1382 206062; +44 1382 206067; [email protected]
, PhD,
Anna L Barnett Cyclacel Inc., James Lindsay Place, Dundee, DD1 5JJ, UK
, PhD,
Steven J McClue Cyclacel Inc., James Lindsay Place, Dundee, DD1 5JJ, UK
, PhD &
Simon R Green Cyclacel Inc., James Lindsay Place, Dundee, DD1 5JJ, UK
, PhD
Pages 131-143 | Published online: 19 Dec 2007

Bibliography

  • Lane DP. Cell immortalization and transformation by the p53 gene. Nature 1984;312:596-7
  • Scherr CJ. Cancer cell cycles. Science 1996;274:1672-7
  • Weinberg RA. The retinoblastoma protein and cell cycle control. Cell 1995;81:323-30
  • Chen YN, Sharma SK, Ramsay TM, et al. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci USA 1999;96:4325-9
  • Zhu Y, Alvarez C, Doll R, et al. Intra-S phase checkpoint activation by direct cdk2 inhibition. Mol Cell Biol 2004;24:6268-77
  • Meijer L, Borgne A, Mulner O, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem 1997;243:527-36
  • Havlicek L, Hanus J, Vesely J, et al. Cytokinin-derived cyclin-dependent kinase inhibitors: synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem 1997;40:408-12
  • 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;243:518-26
  • Fischer PM. Recent advances and new directions in the discovery and development of cyclin-dependent kinase inhibitors. Currt Opin Drug Discov and Dev 2001;4:623-34
  • CNRS: US 6316456 (2001)
  • CYCLACEL LTD.: US 6221873 (2001)
  • CYCLACEL LTD.: US 6703395 (2004)
  • McClue SJ, Blake D, Clarke R, et al. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine). Int J Cancer 2002;102:463-8
  • Meijer L. Chemical inhibitors of cyclin-dependent kinases. Trends Cell Biol 1996;6:393-7
  • Evers DL, Breitenbach JM, Borysko JZ, et al. Inhibition of cyclin-dependent kinase 1 by purines and pyrrolo[2,3-d] pyrimidines does not correlate with antiviral activity. Antimicrob Agents Chemother 2002;46:2470-6
  • Bain J, McLauchlan H, Elliott M, COHEN P. The specificities of protein kinase inhibitors: an update. Biochem J 2003;371:199-204
  • Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427-38
  • Fiebig HH, Maier A, Burger AM. Clonogenic assay with established human tumour xenografts: correlation of in vitro to in vivo activity as a basis for anticancer drug discovery. Eur J Cancer 2004;40:802-20
  • Jackson RC. Theoretical Foundations of Cancer Chemotherapy Introduced by Computer Models. New York, Academic Press; 1992, p. 295
  • Whittaker SR, Walton MI, Garrett MD, Workman P. The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res 2004;64:262-72
  • David-Pfeuty T. Potent inhibitors of cyclin-dependent kinase 2 induce nuclear accumulation of wild-type p53 and nucleolar fragmentation in human untransformed and tumor-derived cells. Oncogene 1999;18:7409-22
  • Mihara M, Shintani S, Kiyota A, et al. Cyclin-dependent kinase inhibitor (roscovitine) suppresses growth and induces apoptosis by regulating Bcl-x in head and neck squamous cell carcinoma cells. Int J Oncol 2002;21:95-101
  • Lacrima K, Valentini A, Lambertini C, et al. In vitro activity of cyclin-dependent kinase inhibitor CYC202 (seliciclib, R-roscovitine) in mantle cell lymphomas. Ann Oncol 2005;16:1169-76
  • Raynaud FI, Nutley BP, Goddard P, et al. Antitumor activity and oral bioavailability of the cyclin dependent kinase inhibitor roscovitine. Clin Cancer Res 2000;6:S4529, abstract 317
  • Tirado OM, Mateo-Lozano S, Notario V. Roscovitine is an effective inducer of apoptosis of Ewing's sarcoma family tumor cells in vitro and in vivo. Cancer Res 2005;65:9320-7
  • LI X, TANAKA K, NAKATANI F, et al. Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects of cyclin dependent kinase inhibitor on Ewing's family tumor cells. Int J Cancer 2005;116:385-94
  • Ortega S, Prieto I, Odajima J, et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 2003;35:25-31
  • Ishihara H, Yoshida T, Kawasaki Y, et al. A new cancer diagnostic system based on a CDK profiling technology. Biochim Biophys Acta 2005;1741:226-33
  • Berthet C, Aleem E, Coppola V, et al. cdk2 knockout mice are viable. Curr Biol 2003;13:1775-85
  • Geng Y, Yu Q, Sicinska E, et al. Cyclin E ablation in the mouse. Cell 2003;114:431-43
  • Su TT, Stumpf J. Promiscuity rules? The dispensability of cyclin E and cdk2. Sci STKE 2004;pe11
  • Tetsu O, McCormick F. Proliferation of cells despite cdk2 inhibition. Cancer Cell 2003;3:233-45
  • Grim JE, Clurman BE. Cycling without cdk2? Trends Cell Biol 2003;13:396-9
  • Hinds PW. Cdk2 dethroned as master of S phase entry. Cancer Cell 2003;3:305-7
  • Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem 2001;276:31793-9
  • Lam LT, Pickeral OK, Peng AC, et al. Genomic scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol 2001;2:research 0041.1 – research 0041.11
  • Lu X, Burgan WE, Cerra MA, et al. Transcriptional significance of flavopiridol-induced tumor cell death. Mol Cancer Ther 2004;3:861-72
  • Shapiro GL. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006;24:1770-83
  • Ljungman M, Paulson MT. The cyclin-dependent kinase inhibitor roscovitine inhibits RNA synthesis and triggers nuclear accumulation of p53 that is unmodified at Ser15 and Lys382. Mol Pharm 2001;60:785-9
  • MacCallum DE, Melville J, Frame S, et al. Seliciclib (CYC202, R-roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res 2005;65:5399-407
  • Alvi AJ, Austen B, Weston VJ, et al. A novel cdk inhibitor, CYC202 (R-roscovitine) overcomes the defect in p53-dependent apoptosis in B-CLL by down-regulation of genes involved in transcription regulation and survival. Blood 2005;105:4484-91
  • Raje N, Kumar S, Hideshima T, et al. Seliciclib (CYC202, roscovitine) a small-molecule cyclin-dependent kinase inhibitor, mediates activity via down-regulation of Mcl-1 in multiple myeloma. Clin Cancer Res 2002;8:3527-38
  • Lu W, Chen L, Peng Y, Chen J. Activation of p53 by roscovitine-mediated suppression of MDM2 expression. Oncogene 2001;20:3206-16
  • Griffiths G, Midgley C, Grabarek J, et al. Identification and characterization of kinase inhibitors that inhibit CDK2, CDK7 and CDK9 activities, induce p53 and result in reduced proliferation and induction of apoptosis of human tumor cells. Proc Am Assoc Cancer Res 2004;45:abstract 837
  • Reynaud FI, Whittaker SR, Fischer PM, et al. In vitro and in vivo pharmacokinetic–pharmacodynamic relationships for the trisunstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res 2005;11:4875-87
  • Nutley BP, Reynaud FI, Wilson SC, et al. Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitor R-roscovitine in the mouse. Mol Cancer Ther 2005;4:125-39
  • Vita M, Abdel-Rehim M, Olufsson S, et al. Tissue distribution, pharmacokinetics and identification of roscovitine metabolites in rat. Eur J Pharm Sci 2005;25:91-103
  • Conroy A, Stockett DE, Nuwayhid S, et al. SNS-032 is a potent and selective CDK2, 7 and 9 inhibitor that drives apoptosis in the multiple myeloma cell line RPMI-8226. Proc Am Assoc Cancer Res 2007;abstract 1815
  • De La Motte S, Gianella-Borradori A. Pharmacokinetic model of R-roscovitine and its metabolite in healthy male subjects. Int J Clin Pharmacol Ther 2004;42:232-9
  • Benson C, White J, De Bono J, et al. A Phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-roscovitine) administered twice daily for 7 days every 21 days. Br J Cancer 2007;96:29-37
  • Faivre S, Pierga JY, Delbado C, et al. A Phase I and pharmacokinetic (pharmacokinetic) trial of CYC202, a novel oral cyclin-dependent kinase (CDK) inhibitor in patients with advanced solid tumours: exploration of three administration schedules. Abstracts, EORTC-NCI-AACR meeting, Boston, USA, 2003
  • Green S, Frame S, Fleming I, et al. Identification of pharmacodynamic biomarkers to support clinical trials of CYC202 (R-roscovitine), a cyclin dependent kinase inhibitor. Proc Am Assoc Cancer Res 2003;44:abstract 2967
  • Barak V, Goike H, Panaretakis KW, Einarsson R. Clinical utility of cytokeratins as tumor markers. Clin Biochem 2004;37:529-40
  • Cummings J, Ransom M, Lacasse E, et al. Method validation and preliminary qualification of pharmacodynamic biomarkers employed to evaluate the clinical efficacy of an antisense compound (AEG35156) targeted to the X-linked inhibitor of apoptosis protein XIAP. Br J Cancer 2006;95:42-8
  • Green SR, Frame S, Watt K, et al. Identification of clinically relevant pharmacodynamic biomarkers in patients treated with the cdk inhibitor CYC202 (R-roscovitine). EORTC-NCI-AACR meeting 2004;abstract 432
  • Frame S, Anderson S, Watt K, et al. Identification and clinical validation of biomarkers to support the development of seliciclib (CYC202). Proc Am Assoc Cancer Res. 2005;46:460
  • Hua F, Cornejo MG, Cardone MH, et al. Effects of bcl-2 levels on Fas signalling-induced caspase-3 activation: molecular genetic tests of computational model predictions. J Immunol 2005;175:985-95
  • Hsieh WS, Peh BK, Loh T, et al. Pharmacodynamic effects of seliciclib (R-roscovitine, CYC202) in patients with undifferentiated nasopharyngeal cancer (NPC) using a window trial design. Abstract # 279 and Poster Presentation 18th EORTC-NCI-AACR Meeting; 2006
  • Wang S, Rowe M, Lundgren E. Expression of the Epstein-Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. Cancer Res 1996;56:4610-13
  • Baba Y, Tsukuda M, Mochimatsu I. Reduced expression of 16 and p27 proteins in nasopharyngeal carcinoma cells. Cancer Detect Prev 2001;25:414-19
  • Coley HM, Shotton CF, Thomas H. Seliciclib (CYC202, R-roscovitine) in combination with cytotoxic agents in human uterine sarcoma cell lines. Anticancer Res 2007;27:273-8
  • Voojis M, Jonkers J, Lyons S, Berns A. Noninvasive imaging of spontaneous retinoblastoma pathway-dependent tumours in mice. Cancer Res 2002;62:1862-7
  • Abal M, Bras-Goncalves R, Juddle JG, et al. Enhanced sensitivity to irinotecan by cdk1 inhibition in the p53-deficient HT29 human colon carcinoma cell line. Oncogene 2004;23:1737-44
  • Fiebig HH, Maier A, Metz T, et al. Schedule-dependency of combining CYC202 (R-roscovitine), a cyclin-dependent kinase inhibitor, with docetaxel in human tumor xenografts in vivo. Clin Cancer Res 2003;9(16 Suppl):abstract C81
  • Frame S, Fleming IN, Watson M, et al. Synergistic combinations between the oral cdk inhibitor, seliciclib and EGFR inhibitors in NSCLC. Proc Amer Assoc Cancer Res 2007;abstract 4003
  • Fleming IN, Watson M, Green SR. Combination analysis between seliciclib (CYC202, R-roscovitine) and other molecularly targeted agents in non-small cell lung cancer. Proc Am Assoc Cancer Res 2006;47:abstract 3838
  • Chen S, Dai Y, Harada H, et al. Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing bak activation and bax translocation. Cancer Res 2007;67:782-91
  • Lin X, Morgan-Lappe S, Huang X, et al. “Seed” analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene 2007;26:3972-9
  • Mody M, Dharker N, Bloomston M, et al. Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to antitumour effects of tumour necrosis factor alpha, CH11 and CYC202. Endocr Relat Cancer 2007;14:305-15
  • Wesierska-Gadek J, Maurer M, Schmid G. Inhibition of farnesyl protein transferase sensitises human MCF-7 breast cancer cells to roscovitine-mediated cell cycle arrest. J Cell Biochem 2007;[Epub ahead of print]
  • Maggiorella L, Deutsch E, Frascogna V, et al. Enhancement of radiation response by roscovitine in human breast carcinoma in vitro and in vivo. Cancer Res 2003;63:2513-17
  • Wu K, Wang C, D'Amico M, et al. Flavopiridol and trastuzumab synergistically inhibit proliferation of breast cancer cells: association with selective cooperative inhibition of cyclin D1-dependent kinase and Akt signalling pathways. Mol Cancer Ther 2002;1:695-706
  • Rosner GL, Stadler W, Ratain MJ. Randomised discontinuation design: application to cytostatic antineoplastic agents. J Clin Oncol 2002;20:4478-84
  • Schang LM. Cyclin-dependent kinases as cellular targets for antiviral drugs. J Antimicrob Chemother 2002;50:779-92
  • Shankland SJ, Wolf G. Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. Am J Physiol Renal Physiol 2000;278:F515-29
  • Rossi AG, Sawatzky DA, Walker A, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med 2006;12:1056-64
  • Zoja C, Casiraghi F, Conti S, et al. Cyclin-dependent kinase inhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus. Arthritis Rheum 2007;56:1629-37
  • Bukanov NO, Smith LA, Klinger KW, et al. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 2006;444:949-52
  • Smith PD, O'Hare MJ, Park DS. Emerging pathogenic role for cyclin-dependent kinases in neurodegeneration. Cell Cycle 2004;3:289-91

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.