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An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor

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Abstract

The spindle assembly checkpoint is a cell cycle surveillance mechanism that ensures the proper separation of chromosomes prior to cell division at mitosis. Aurora kinases play critical roles in mitotic progression and hence small-molecule inhibitors of Aurora kinases have been developed as a new class of potential anti-cancer drugs. In this paper we present for the first time an integrated pharmacokinetic–pharmacodynamic model of the functional effects of CYC116 (a known inhibitor of Aurora kinases A and B) on the spindle assembly checkpoint. We use the model to simulate two common experimental systems: cell culture and p.o. dosing of mice and present predictions of the effects of CYC116 for a range of doses and drug scheduling regimes. The model reveals that a critical peak drug concentration is required to cause aberrant kinetochore-microtubule attachments. The model also predicts that provided this threshold concentration is exceeded, a high total oral dose causes a high number of aberrant attachments within any given damaged cell. However, the proportion of cells which enter anaphase with aberrant attachments is associated with the total length of time for which the plasma concentration is maintained above the threshold. Moreover, our model reveals that the length of prometaphase/metaphase is a nonlinear function of drug dose and this time period can be extended or shortened. Finally, a strong saturation effect on CYC116 efficacy is predicted by the model. We discuss how these predictions may have implications for further drug trials using CYC116 and other similar AK inhibitors.

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References

  1. Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, Mortlock A, Keen N, Taylor SS (2003) Aurora B coupleds chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 161:267–280

    Article  CAS  PubMed  Google Scholar 

  2. Kops GJ, Weaver BA, Cleveland DW (2005) On the road to cancer: aneuploidy and the mitotic checkpoint. Nature Rev Cancer 5:773–785

    Article  CAS  Google Scholar 

  3. Weaver BA, Cleveland DW (2005) Decoding the links between mitosis, cancer, and chemotherapy: the mitotic checkpoint, adaptation, and cell death. Cancer Cell 8:7–12

    Article  CAS  PubMed  Google Scholar 

  4. Li JJ, Li SA (2006) Mitotic kinases: the key to duplication, segregation, and cytokinetic errors, chromosomal instability, and oncogenesis. Pharmacol Ther 111:974–998

    Article  CAS  PubMed  Google Scholar 

  5. Sear RP, Howard M (2006) Modeling dual pathways for the metazoan spindle assembly checkpoint. Proc Natl Acad Sci USA 103:16758–16763

    Article  CAS  PubMed  Google Scholar 

  6. Fry AM, Yamano H (2008) Under arrest in mitosis: Cdc20 dies twice. Nat Cell Biol 10:1385–1387

    Article  CAS  PubMed  Google Scholar 

  7. Nilsson J, Yekezare M, Minshull J, Pines J (2008) The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction. Nat Cell Biol 10:1411–1420

    Article  CAS  PubMed  Google Scholar 

  8. Nigg EA (2001) Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2:21–32

    Article  CAS  PubMed  Google Scholar 

  9. Adams RR, Maiato H, Earnshaw WC, Carmena M (2001) Essential roles of Drosophila inner centromere protein (INCENP) and Aurora B in Histone H3 phosphorylation, metaphase chromosome alignment, kinetochore disjunction, and chromosome segregation. J Biol Chem 15:865–880

    Google Scholar 

  10. de Castro IP, de Carcer G, Malumbres M (2007) A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis 28:899–912

    Article  Google Scholar 

  11. Giet R, Petretti C, Prigent C (2005) Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 15:241–250

    Article  CAS  PubMed  Google Scholar 

  12. Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD (1998) A homologue of Drosophila Aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17:3052–3065

    Article  CAS  PubMed  Google Scholar 

  13. Zhou H, Kuang J, Zhong L, Juo KW, Gray J, Sahin A, Brinkley B, Sen S (1998) Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193

    Article  CAS  PubMed  Google Scholar 

  14. Tchatchou S, Wirtenberger M, Hemminki K, Sutter C, Meindl A, Wappenschmidt B, Kiechle M, Bugert P, Schmutzler RK, Bartram CR, Burwinkel B (2007) Aurora kinases A and B and familial breast cancer risk. Cancer Lett 247:266–272

    Article  CAS  PubMed  Google Scholar 

  15. Gu J, Gong Y, Huang M, Ju C, Spitz MR, Wu X (2007) Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in causasians. Carcinogenesis 28:350–355

    Article  CAS  PubMed  Google Scholar 

  16. Katayama H, Ota T, Jisaki F, Ueda Y, Tanaka T, Odashima S, Suzuki F, Terada Y, Tatsuka M (1999) Mitotic kinase expression and colorectal cancer progression. J Natl Cancer Inst 91:1160–1162

    Article  CAS  PubMed  Google Scholar 

  17. Sorrentino R, Libertini S, Pallante PL, Troncone G, Palombini L, Bavetsias V, Spalletti-Cernia D, Laccetti P, Linardopoulos S, Chieffi P, Fusco A, Portell G (2004) Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 90:928–935

    Article  PubMed  Google Scholar 

  18. Kimura M, Matsuda Y, Yoshioka T, Okano Y (1999) Cell cycle-dependent expression and centrosome localization of a third human Aurora/Ip11-related protein kinase, AIK3. J Biochem 274:7334–7340

    CAS  Google Scholar 

  19. Pollard JR, Mortimore M (2009) Discovery and development of Aurora kinase inhibitors as anticancer agents. J Med Chem 52:2629–2651

    Article  CAS  PubMed  Google Scholar 

  20. Wang S, Midgley CA, Scaërou F, Grabarek JB, Griffiths G, Jackson W, Kontopidis G, McClue SJ, McInnes C, Meades C, Mezna M, Plater A, Stuart I, Thomas MP, Wood G, Clarke RG, Blake DG, Zheleva DI, Lane DP, Jackson RC, Glover DM, Fischer PM. Discovery of A-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine Aurora kinase inhibitors. J Med Chem (to appear)

  21. Mistry HB, MacCallum DE, Jackson RC, Chaplain MAJ, Davidson FA (2008) Modeling the temporal evolution of the spindle assembly checkpoint and role of Aurora B kinase. Proc Natl Acad Sci USA 105:20215–20220

    Article  CAS  PubMed  Google Scholar 

  22. Mistry HB, MacCallum DE, Jackson RC, Chaplain MAJ, Davidson FA (2010) A pharmacodynamic model of Aurora kinase inhibitors in the spindle assembly checkpoint. Front Biosci 15:249–258

    Article  CAS  PubMed  Google Scholar 

  23. Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayama T, Graham JA, Demur C, Hercend T, Diu-Hercend A, Su M, Golec JM, Miller KM (2004) VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 10:262–267

    Article  CAS  PubMed  Google Scholar 

  24. Ferrari S, Marin O, Pagano MA, Meggio F, Hess D, El-Shemerly M, Krystyniak A, Pinna LA (2005) Aurora-A site specificity: a study with synthetic peptide substrates. Biochem J 390:293–302

    Article  CAS  PubMed  Google Scholar 

  25. Galvin KM, Huck J, Burenkova O, Burke K, Bowman D, Shinde V, Stringer B, Zhang M, Manfredi M, Meetze K (June 2006) Preclinical pharmacodynamic studies of Aurora A inhibition by MLN8054. In: ASCO annual meeting proceedings. American Society of Clinical Oncology, Abstract no. 18S:13059

  26. Griffiths G, Scaerou F, Sorrel D, Duckmanton A, Tosh C, Lewis S, Migdley C, McClue S, Jackson W, MacCallum D, Thomas M, Wang S, Fisher P, Glover D, Zheleva D (April 2008) Anti-tumor activity of CYC116, a novel small molecule inhibitor or Aurora kinases and VEGFR2. In: Proceedings of the 99th AACR annual meeting, San Diego, CA. American Association for Cancer Research, Philadelphia, PA, Abstract No. 5644

  27. Griffiths G, Tosh C, Kollareddy M, Duckmanton A, Lewis S, Scaerou F, Zheleva D (April 2008) The basis of cell sensitivity to Aurora A/B inhibitors. In: Proceedings of the 99th AACR annual meeting, San Diego, CA. American Association for Cancer Research, Philadelphia, PA, Abstract No. 651

  28. Gabrielsson J, Weiner D (2000) Pharmacokinetic and pharmacodynamic data analysis: concepts and applications. Swedish Pharmaceutical Press, Stockholm

    Google Scholar 

  29. Cheng Y, Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108

    Article  CAS  PubMed  Google Scholar 

  30. Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, Saya H (2003) Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 278:51786–51795

    Article  CAS  PubMed  Google Scholar 

  31. Portier N, Audhya A, Maddox PS, Green RA, Dammermann A, Desai A, Oegema K (2007) A microtubule-independent role for entrosomes and Aurora A in nuclear envelope breakdown. Dev Cell 12:515–529

    Article  CAS  PubMed  Google Scholar 

  32. Kunitoku N, Sasayama T, Marumoto T, Zhang D, Honda S, Kobayashi O, Hatakeyama K, Ushio Y, Saya H, Hirota T (2003) CENP-A phosphorylation by Aurora-A in prophase is required for enrichment of Aurora B at inner centromeres and for kinetochore function. Dev Cell 5:853–864

    Article  CAS  PubMed  Google Scholar 

  33. Knowlton AL, Lan W, Stukenberg P (2006) Aurora B is enriched at merotelic attachment sites, where it regulates MCAK. Curr Biol 16:1705–1710

    Article  CAS  PubMed  Google Scholar 

  34. Hauf S, Cole RW, LaTerra S, Zimmer C, Schnapp G, Walter R, Heckel A, van Meel J, Rieder CL, Peters JM (2003) The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Biol Chem 16:281–294

    Google Scholar 

  35. Tanaka TU, Rachidi N, Janke C, Pereira G, Galova M, Schiebel E, Stark MJR, Nasmyth K (2002) Evidence that the Ipl1-Sli15 (Aurora kinase-INCENP) complex promotes chromosome bi-orientation by altering kinetochore spindle pole connections. Cell 108:317–329

    Article  CAS  PubMed  Google Scholar 

  36. Vignoren S, Prieto S, Bernis C, Labbe JC, Castro A, Lorca T (2004) Kinetochore localization of spindle checkpoint proteins: who controls whom? Mol Biol Cell 15:4584–4596

    Article  Google Scholar 

  37. Fu J, Bian M, Jiang Q, Zhang C (2007) Roles of Aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 5:1–10

    Article  CAS  PubMed  Google Scholar 

  38. Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM, Keen J, Taylor SS (2006) Validating Aurora B as an anti-cancer drug target. J Cell Sci 119:3664–3675

    Article  CAS  PubMed  Google Scholar 

  39. Wilkinson RW, Odedra R, Heaton SP, Wedge SR, Keen NJ, Crafter C, Foster JR, Brady MC, Bigley A, Brown E, Byth KF, Barrass NC, Mundt KE, Foote KM, Heron NM, Jung FH, Mortlock AA, Boyle FT, Green S (2007) AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor zenograft growth by inducing apoptosis. Clin Cancer Res 13:3682–3688

    Article  CAS  PubMed  Google Scholar 

  40. Lohel M, Ibrahim B, Diekmann S, Dittrich P (2009) The role of localization in the operation of the mitotic spindle assembly checkpoint. Cell Cycle 8:2650–2660

    CAS  PubMed  Google Scholar 

  41. Welling PG (1986) Pharmacokinetics: Processes and mathematics. American Chemical Society, Washington

    Google Scholar 

  42. Hajduch M, Vydra D, Dzubak P, Dziechciarkova M, Stuart I, Zheleva D (April 2008) In vivo mode of action of CYC116, a novel small molecule inhibitor of Aurora kinases and VEGFR2. In: Proceedings of the 99th AACR annual meeting, San Diego, CA. American Association for Cancer Research: Philadelphia, PA, Abstract no. 5645

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Acknowledgments

This work was supported by Engineering and Physical Sciences Research Council grant EP/D04859 under the Mathematics for Business Scheme.

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Authors and Affiliations

  1. Division of Mathematics, University of Dundee, Dundee, DD1 4HN, UK

    Hiroko Kamei & Fordyce A. Davidson

  2. Pharmacometrics Ltd, Cambridge, UK

    Robert C. Jackson

  3. Cyclacel Ltd., James Lindsay Place, Dundee, DD1 5JJ, UK

    Daniella Zheleva

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  1. Hiroko Kamei
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  2. Robert C. Jackson
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  3. Daniella Zheleva
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  4. Fordyce A. Davidson
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Correspondence to Fordyce A. Davidson.

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Kamei, H., Jackson, R.C., Zheleva, D. et al. An integrated pharmacokinetic–pharmacodynamic model for an Aurora kinase inhibitor. J Pharmacokinet Pharmacodyn 37, 407–434 (2010). https://doi.org/10.1007/s10928-010-9166-0

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  • DOI: https://doi.org/10.1007/s10928-010-9166-0

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