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ZM447439

ZM447439 (ZM) is a potent and selective inhibitor of aurora-A and -B kinase with putative anti-tumoral activity. Inhibitors of aurora kinases were shown to induce apoptosis in vitro and in vivo. ZM induced apoptosis in a concentration- and time-dependent manner. ZM-induced apoptosis was associated with an upregulation of p53, breakdown of the mitochondrial membrane potential (DeltaPsim) and activation of caspase-3. To precisely define key components for ZM-induced apoptosis, knockout cells lacking p53, Bak, Bax or both Bak and Bax were used. Lack of p53 reduced ZM-induced apoptosis and breakdown of DeltaPsim, while lack of Bak, Bax or both almost completely inhibited apoptosis and breakdown of DeltaPsim. Since no difference in apoptosis induction was detectable between HCT-116 cells lacking Bak, Bax or both, apoptosis induction depended non-redundantly on both Bak and Bax. Phenomenally, ZM induced notable polyploidization in all examined cells, especially in p53-/- cells. A correlation between polyploidization and apoptosis was observed in wild-type, and also in p53-/- cells, albeit with a modest extent of apoptosis. Moreover, in Bak-/-, Bax-/- and Bak/Bax-/- cells apoptosis was totally inhibited in spite of the strongest polyploidization, suggesting apoptosis may be a secondary event following polyploidization in HCT-116 cells. Thus ZM-induced apoptosis depends not only on polyploidization, but also on the intracellular apoptotic signaling [source: Biochem Pharmacol. 2010 Jan 15;79(2):122-9. Epub 2009 Aug 15].

Current developer:    AstraZeneca UK Ltd

 1: Kreis NN, Sanhaji M, Krämer A, Sommer K, Rödel F, Strebhardt K, Yuan J. Restoration of the tumor suppressor p53 by downregulating cyclin B1 in human papillomavirus 16/18-infected cancer cells. Oncogene. 2010 Jul 26. [Epub ahead of print] PubMed PMID: 20661218.

2: Lane SI, Chang HY, Jennings PC, Jones KT. The Aurora kinase inhibitor ZM447439 accelerates first meiosis in mouse oocytes by overriding the spindle assembly checkpoint. Reproduction. 2010 Jul 21. [Epub ahead of print] PubMed PMID: 20660090.

3: Crispi S, Fagliarone C, Biroccio A, D'Angelo C, Galati R, Sacchi A, Vincenzi B, Baldi A, Verdina A. Antiproliferative effect of Aurora kinase targeting in mesothelioma. Lung Cancer. 2010 Apr 3. [Epub ahead of print] PubMed PMID: 20371132.

4: Jeong YS, Cho S, Park JS, Ko Y, Kang YK. Phosphorylation of serine-10 of histone H3 shields modified lysine-9 selectively during mitosis. Genes Cells. 2010 Jan 13. [Epub ahead of print] PubMed PMID: 20070858.

5: Georgieva I, Koychev D, Wang Y, Holstein J, Hopfenmüller W, Zeitz M, Grabowski P. ZM447439, a novel promising aurora kinase inhibitor, provokes antiproliferative and proapoptotic effects alone and in combination with bio- and chemotherapeutic agents in gastroenteropancreatic neuroendocrine tumor cell lines. Neuroendocrinology. 2010;91(2):121-30. Epub 2009 Nov 14. PubMed PMID: 19923785.

6: Suzuki T, Miyazaki K, Kita K, Ochi T. Trivalent dimethylarsenic compound induces histone H3 phosphorylation and abnormal localization of Aurora B kinase in HepG2 cells. Toxicol Appl Pharmacol. 2009 Dec 15;241(3):275-82. Epub 2009 Aug 28. PubMed PMID: 19716834.

7: Li M, Jung A, Ganswindt U, Marini P, Friedl A, Daniel PT, Lauber K, Jendrossek V, Belka C. Aurora kinase inhibitor ZM447439 induces apoptosis via mitochondrial pathways. Biochem Pharmacol. 2010 Jan 15;79(2):122-9. Epub 2009 Aug 15. PubMed PMID: 19686703.

8: Kaestner P, Stolz A, Bastians H. Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells. Mol Cancer Ther. 2009 Jul;8(7):2046-56. Epub 2009 Jul 7. PubMed PMID: 19584233.

9: Shuda K, Schindler K, Ma J, Schultz RM, Donovan PJ. Aurora kinase B modulates chromosome alignment in mouse oocytes. Mol Reprod Dev. 2009 Nov;76(11):1094-105. PubMed PMID: 19565641.

10: Bekier ME, Fischbach R, Lee J, Taylor WR. Length of mitotic arrest induced by microtubule-stabilizing drugs determines cell death after mitotic exit. Mol Cancer Ther. 2009 Jun;8(6):1646-54. Epub 2009 Jun 9. PubMed PMID: 19509263.

11: Dreier MR, Grabovich AZ, Katusin JD, Taylor WR. Short and long-term tumor cell responses to Aurora kinase inhibitors. Exp Cell Res. 2009 Apr 15;315(7):1085-99. Epub 2009 Feb 20. PubMed PMID: 19233169.

12: Kosik A, Bekier ME, Katusin JD, Kaur H, Zhou X, Diakonova M, Chadee DN, Taylor WR. Investigating the role of Aurora kinases in RAS signaling. J Cell Biochem. 2009 Jan 1;106(1):33-41. PubMed PMID: 19009561.

13: Ganguly A, Bhattacharya R, Cabral F. Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement. Cell Cycle. 2008 Oct;7(20):3187-93. Epub 2008 Oct 18. PubMed PMID: 18843200; PubMed Central PMCID: PMC2677962.

14: Sun F, Handel MA. Regulation of the meiotic prophase I to metaphase I transition in mouse spermatocytes. Chromosoma. 2008 Oct;117(5):471-85. Epub 2008 Jun 18. PubMed PMID: 18563426; PubMed Central PMCID: PMC2737826.

15: Girdler F, Sessa F, Patercoli S, Villa F, Musacchio A, Taylor S. Molecular basis of drug resistance in aurora kinases. Chem Biol. 2008 Jun;15(6):552-62. PubMed PMID: 18559266.

16: Macarulla T, Ramos FJ, Tabernero J. Aurora kinase family: a new target for anticancer drug. Recent Pat Anticancer Drug Discov. 2008 Jun;3(2):114-22. Review. PubMed PMID: 18537754.

17: Long ZJ, Xu J, Yan M, Zhang JG, Guan Z, Xu DZ, Wang XR, Yao J, Zheng FM, Chu GL, Cao JX, Zeng YX, Liu Q. ZM 447439 inhibition of aurora kinase induces Hep2 cancer cell apoptosis in three-dimensional culture. Cell Cycle. 2008 May 15;7(10):1473-9. Epub 2008 Mar 12. PubMed PMID: 18418083.

18: Wang LH, Yan M, Xu DZ, Cao JX, Zhu XF, Zeng YX, Liu Q. Requirement of aurora-A kinase in astral microtubule polymerization and spindle microtubule flux. Cell Cycle. 2008 Apr 15;7(8):1104-11. Epub 2008 Feb 11. PubMed PMID: 18414060.

19: Walsby E, Walsh V, Pepper C, Burnett A, Mills K. Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts. Haematologica. 2008 May;93(5):662-9. Epub 2008 Mar 26. PubMed PMID: 18367484.

20: Swain JE, Ding J, Wu J, Smith GD. Regulation of spindle and chromatin dynamics during early and late stages of oocyte maturation by aurora kinases. Mol Hum Reprod. 2008 May;14(5):291-9. Epub 2008 Mar 18. PubMed PMID: 18353803; PubMed Central PMCID: PMC2408935.

21: Famulski JK, Chan GK. Aurora B kinase-dependent recruitment of hZW10 and hROD to tensionless kinetochores. Curr Biol. 2007 Dec 18;17(24):2143-9. Epub 2007 Dec 6. PubMed PMID: 18065224.

22: Tyler RK, Shpiro N, Marquez R, Eyers PA. VX-680 inhibits Aurora A and Aurora B kinase activity in human cells. Cell Cycle. 2007 Nov 15;6(22):2846-54. Epub 2007 Aug 27. PubMed PMID: 18032922.

23: Agnese V, Bazan V, Fiorentino FP, Fanale D, Badalamenti G, Colucci G, Adamo V, Santini D, Russo A. The role of Aurora-A inhibitors in cancer therapy. Ann Oncol. 2007 Jun;18 Suppl 6:vi47-52. Review. PubMed PMID: 17591831.

24: Ikezoe T, Yang J, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H. A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia. Mol Cancer Ther. 2007 Jun;6(6):1851-7. Epub 2007 May 31. PubMed PMID: 17541033.

25: Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, Komatsu N, Bandobashi K, Togitani K, Koeffler HP, Taguchi H, Yokoyama A. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood. 2007 Sep 15;110(6):2034-40. Epub 2007 May 10. PubMed PMID: 17495131.

26: Kim KW, Mutter RW, Willey CD, Subhawong TK, Shinohara ET, Albert JM, Ling G, Cao C, Gi YJ, Lu B. Inhibition of survivin and aurora B kinase sensitizes mesothelioma cells by enhancing mitotic arrests. Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1519-25. PubMed PMID: 17394948.

27: Keady BT, Kuo P, Martínez SE, Yuan L, Hake LE. MAPK interacts with XGef and is required for CPEB activation during meiosis in Xenopus oocytes. J Cell Sci. 2007 Mar 15;120(Pt 6):1093-103. PubMed PMID: 17344432.

28: Kaur H, Stiff AC, Date DA, Taylor WR. Analysis of mitotic phosphorylation of borealin. BMC Cell Biol. 2007 Jan 22;8:5. PubMed PMID: 17241471; PubMed Central PMCID: PMC1794407.

29: Gabrielli B, Chau YQ, Giles N, Harding A, Stevens F, Beamish H. Caffeine promotes apoptosis in mitotic spindle checkpoint-arrested cells. J Biol Chem. 2007 Mar 9;282(10):6954-64. Epub 2006 Dec 20. PubMed PMID: 17182611.

30: Vischioni B, Oudejans JJ, Vos W, Rodriguez JA, Giaccone G. Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell lung carcinoma patients. Mol Cancer Ther. 2006 Nov;5(11):2905-13. PubMed PMID: 17121938.

31: Wang Q, Wang CM, Ai JS, Xiong B, Yin S, Hou Y, Chen DY, Schatten H, Sun QY. Histone phosphorylation and pericentromeric histone modifications in oocyte meiosis. Cell Cycle. 2006 Sep;5(17):1974-82. Epub 2006 Sep 1. PubMed PMID: 16969090.

32: Wang Y, Toppari J, Parvinen M, Kallio MJ. Inhibition of Aurora kinases perturbs chromosome alignment and spindle checkpoint signaling in rat spermatocytes. Exp Cell Res. 2006 Nov 1;312(18):3459-70. Epub 2006 Aug 12. PubMed PMID: 16962097.

33: Cimini D, Wan X, Hirel CB, Salmon ED. Aurora kinase promotes turnover of kinetochore microtubules to reduce chromosome segregation errors. Curr Biol. 2006 Sep 5;16(17):1711-8. PubMed PMID: 16950108.

34: Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM, Keen NJ, Taylor SS. Validating Aurora B as an anti-cancer drug target. J Cell Sci. 2006 Sep 1;119(Pt 17):3664-75. Epub 2006 Aug 15. PubMed PMID: 16912073.

35: Thomas NR. Histone post-translational modification: from discovery to the clinic. IDrugs. 2006 Jun;9(6):398-401. PubMed PMID: 16752306.

36: Gadea BB, Ruderman JV. Aurora B is required for mitotic chromatin-induced phosphorylation of Op18/Stathmin. Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4493-8. Epub 2006 Mar 14. PubMed PMID: 16537398; PubMed Central PMCID: PMC1401233.

37: Jelínková L, Kubelka M. Neither Aurora B activity nor histone H3 phosphorylation is essential for chromosome condensation during meiotic maturation of porcine oocytes. Biol Reprod. 2006 May;74(5):905-12. Epub 2006 Feb 1. PubMed PMID: 16452462.

38: Morrow CJ, Tighe A, Johnson VL, Scott MI, Ditchfield C, Taylor SS. Bub1 and aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20. J Cell Sci. 2005 Aug 15;118(Pt 16):3639-52. Epub 2005 Jul 26. PubMed PMID: 16046481.

39: Yang H, Burke T, Dempsey J, Diaz B, Collins E, Toth J, Beckmann R, Ye X. Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase. FEBS Lett. 2005 Jun 20;579(16):3385-91. PubMed PMID: 15922328.

40: Gadea BB, Ruderman JV. Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts. Mol Biol Cell. 2005 Mar;16(3):1305-18. Epub 2004 Dec 22. PubMed PMID: 15616188; PubMed Central PMCID: PMC551494.

41: Ditchfield C, Keen N, Taylor SS. The Ipl1/Aurora kinase family: methods of inhibition and functional analysis in mammalian cells. Methods Mol Biol. 2005;296:371-81. PubMed PMID: 15576945.

42: Doggrell SA. Dawn of Aurora kinase inhibitors as anticancer drugs. Expert Opin Investig Drugs. 2004 Sep;13(9):1199-201. Review. PubMed PMID: 15330750.

43: Ditchfield C, Johnson VL, Tighe A, Ellston R, Haworth C, Johnson T, Mortlock A, Keen N, Taylor SS. Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol. 2003 Apr 28;161(2):267-80. PubMed PMID: 12719470; PubMed Central PMCID: PMC2172902.