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Danusertib (formerly PHA-739358) – A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor

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Small Molecules in Oncology

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 184))

Abstract

The Aurora kinases belong to a family of highly conserved serine/threonine protein kinases. They play an essential role as key mitotic regulators, controlling entry into mitosis, centrosome function, chromosome assembly, and segregation. As many other regulators of mitosis, Aurora kinases are frequently found to be aberrantly overexpressed in cancer cells. Therefore, these proteins have become an attractive target for the development of new anticancer therapies. In fact, several small-molecule inhibitors of Aurora kinases have already been developed and some of them have shown promising clinical efficacy in a number of human tumors in Phase I and II clinical trials. Among those, one of the most advanced clinical compound currently is Danusertib (formerly PHA-739358), which exhibits inhibitory activity against all known Aurora kinases as well as other cancer-relevant kinases such as the Bcr-Abl tyrosine kinase, including its multidrug-resistant T315I mutant. This mutation is responsible for up to 25% of all clinically observed resistances in CML patients undergoing Imatinib therapy. However, this particular mutation is predicted to play an even more important clinical role in the future, since in addition to Imatinib, it also confers resistance to second-generation Bcr-Abl inhibitors such as Nilotinib, Dasatinib, and Bosutinib. Therefore, combined Aurora and Bcr-Abl inhibition (the latter including high-grade resistance conferring mutations) with compounds such as Danusertib represents a promising new strategy for treatment of Bcr-Abl positive leukemias, especially those in second and third line of treatment.

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References

  • Adams RR, Carmena M, Earnshaw WC (2001a) Chromosomal passengers and the (Aurora) ABCs of mitosis. Trends Cell Biol 11:49–54

    Article  PubMed  CAS  Google Scholar 

  • Adams RR, Eckley DM, Vagnarelli P, Wheatley SP, Gerloff DL, Mackay AM, Svingen PA, Kaufmann SH, Earnshaw WC (2001b) Human INCENP colocalizes with the Aurora-B/AIRK2 kinase on chromosomes and is overexpressed in tumour cells. Chromosoma 110:65–74

    Article  PubMed  CAS  Google Scholar 

  • Bernard M, Sanseau P, Henry C, Couturier A, Prigent C (1998) Cloning of STK13, a third human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on chromosome 19q13.3-ter. Genomics 53:406–409

    Article  PubMed  CAS  Google Scholar 

  • Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Günther 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  PubMed  CAS  Google Scholar 

  • Bongarzone I, Vigneri P, Mariani L, Collini P, Pilotti S, Pierotti MA (1998) RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Clin Cancer Res 4:223–228

    PubMed  CAS  Google Scholar 

  • Boss D, Beijnen JH, Schellens JH (2009) Clinical Experience with Aurora Kinase Inhibitors: A Review. Oncologist 14: 780–793

    Google Scholar 

  • Carmena M, Earnshaw WC (2003) The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 4:842–854

    Article  PubMed  CAS  Google Scholar 

  • Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, Degrassi A, Texido G, Rocchetti M, Vianello P, Rusconi L, Storici P, Zugnoni P, Arrigoni C, Marsiglio A, Ballinari D, Pesenti E, Fancelli D, Moll J (2007) Danusertib , a potent inhibitor of aurora kinases with a selective target inhibition profile relevant to cancer. Mol Cancer Ther 6:3158–3168

    Article  PubMed  CAS  Google Scholar 

  • Carpinelli P, Moll J (2007) Aurora kinases and their inhibitors: more than one target and one drug. Adv Exp Med Biol 610:54–73

    Article  Google Scholar 

  • Castro A, Arlot-Bonnemains Y, Vigneron S, Labbe JC, Prigent C, Lorca T (2002a) APC/Fizzy-related targets Aurora A kinase for proteolysis. EMBO Rep 3:457–462

    Article  PubMed  CAS  Google Scholar 

  • Castro A, Vigneron S, Bernis C, Labbe JC, Prigent C, Lorca T (2002b) The D-Box-activating domain (DAD) is a new proteolysis signal that stimulates the silent D-Box sequence of Aurora A. EMBO Rep 3:1209–1214

    Article  PubMed  CAS  Google Scholar 

  • Cheetam GMT, Knegtel RMA, Coll JT, Renwick SB, Swenson L, Weber P, Lippke JA, Austen DA (2000) Crystal structure of Aurora-2, an oncogenic serine/threonine kinase. J Biol Chem 277: 42419–42422

    Article  Google Scholar 

  • Chieffi P, Cozzolino L, Kisslinger A, Libertini S, Staibano S, Mansueto G, De Rosa G, Vilacci A, Vitale M, Linardopoulos S, Portella G, Tramontano D (2006) Aurora B expression directly correlates with prostate cancer malignancy and influences prostate cell proliferation. Prostate 66:326–333

    Article  PubMed  CAS  Google Scholar 

  • Cohen RB, Jones SF, Aggarwal C, von Mehren M, Cheng J, Spigel DR, Greco FA, Mariani M, Rocchetti M, Ceruti R, Comis S, Laffranchi B, Moll J, Burris HA (2009) A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-hour Infusion With and Without G-CSF in a 14-day Cycle in Patients with Advanced Solid Tumors. Clin Cancer Res.; in press

    Google Scholar 

  • Cortes J, Roboz GJ, Kantarjian H, Feldman E, Karp J, Pollack A, Sandy K, Rao N, Akinaga S, Levis M (2007) A phase I dose escalation study of KW-2449, an oral multikinase inhibitor against FLT3, ABL, FGFR1, and Aurora in patients with relapsed/refractory AML, treatment resistant/intolerant CML, ALL, MDS. Blood 110:abstr. 909

    Google Scholar 

  • De Jonge M (2006) A phase I dose-escalation study of Danusertib administered as a 6-hour infusion on days 1, 8, and 15 every 4 weeks in patients with advanced/metastatic solid tumors. VIII Congress of the Italian Association of Medical Oncology (IAOM), Milan, Italy

    Google Scholar 

  • Dewar H, Tanaka K, Nasmyth K, Tanaka TU (2004) Tension between two kinetochores siffices for their biorientation on the mitotic spindle. Nature 428:93–97

    Article  PubMed  CAS  Google Scholar 

  • DiCioccio RA, Song H, Waterfall C, Kimura MT, Nagase H, McGuire V, Hogdall E, Shah MN, Luben RN, Easton DF, Jacobs IJ, Ponder BAJ, Whittemore AS, Gayther SA, Pharoah PDP, Kruger-Kjaer S (2004) STK15 polymorphisms and association with risk of invasive ovarian cancer. Cancer Epidemiol Biomark Prev 13: 1589–1594

    Google Scholar 

  • Dionne CA, Camoratto AM, Jani JP, Emerson E, Neff N, Vaught JL, Murakata C, Djakiew D, Lamb J, Bova S, George D, Isaacs JT (1998) Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587). Clin Cancer Res 4:1887–1898

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Egan KM, Newcomb PA, Ambrosone CB, Trentham-Dietz A, Titus-Ernstoff L, Hampton JM, Kimura MT, Nagase H (2004) STK15 polymorphism and breast cancer risk in a population-based study. Carcinogenesis 25:2149–2153

    Article  PubMed  CAS  Google Scholar 

  • Ewart-Toland A, Briassouli P, de Koning JP, Mao JH, Yuan J, Chan F, MacCarthy-Morrogh L, Ponder BA, Nagase H, Burn J, Ball S, Almeida M, Linardopoulos S, Balmain A (2003) Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet 34:403–412

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Galvin KM, Huck J, Burenkova O, Burke K, Bowman D, Shinde V, Stringer B, Zhang M, Manfredi M, Meetze K (2006) Preclinical pharmacodynamic studies of Aurora-A inhibition by MLN8054. J Clin Oncol 24(20 Suppl): 13059

    Google Scholar 

  • Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN, Gandara DR (2008) Aurora Kinases as Anticancer Drug Targets. Clin Cancer Res 14: 1639–1648

    Article  PubMed  CAS  Google Scholar 

  • Giet R, Glover DM (2001) Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J Cell Biol 152: 669–682

    Article  PubMed  CAS  Google Scholar 

  • Giet R, Prigent C (1999) Aurora/Ipl 1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci 112:3591–3601

    PubMed  CAS  Google Scholar 

  • Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ (2007) MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 109: 500–502

    Article  PubMed  CAS  Google Scholar 

  • Glover DM, Leibowitz MH, McLean DA, Parry H (1995) Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 81:95–105

    Article  PubMed  CAS  Google Scholar 

  • Gontarewicz A, Balabanov S, Keller G, Colombo R, Graziano A, Pesenti E, Benten D, Bokemeyer C, Fiedler W, Moll J, Brümmendorf TH (2008) Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor Danusertib is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood 111:4355–4364

    Article  PubMed  CAS  Google Scholar 

  • Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O’Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR (2007) Patterns of somatic mutation in human cancer genomes. Nature 446:153–158

    Article  PubMed  CAS  Google Scholar 

  • Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, Fiorica JV, Nicosia SV, Cheng JQ (2003) activation and over-expression of centrosome kinase BTAK/Aurora-A in human ovarian cancer. Clin Cancer Res 9:1420–1426

    PubMed  CAS  Google Scholar 

  • Gurley LR, D’Anna JA, Barham SS, Deaven LL, Tobey RA (1978) Histone phosphorylation and chromatin structure during mitosis in Chinese hamster cells. Eur J Biochem 84:1–15

    Article  PubMed  CAS  Google Scholar 

  • Hampton T (2007) New blood cancer therapies under study. JAMA 297:457–458

    Article  PubMed  CAS  Google Scholar 

  • Han H, Bearss DJ, Browne LW, Calaluce R, Nagle RB, Von Hoff DD (2002) Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res 62: 2890–2896

    PubMed  CAS  Google Scholar 

  • Harrington EA, Bebbington D, Moore J, Rasmussen RK, Ajose-Adeogun AO, Nakayam 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  PubMed  CAS  Google Scholar 

  • 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 Cell Biol 161:281–294

    Article  PubMed  CAS  Google Scholar 

  • Hu HM, Chuang CK, Lee MJ, Tseng TC, Tang TK (2000) Genomic organization, expression, and chromosome localization of a third aurora-related kinase gene, Aie1. DNA Cell Biol 19: 679–688

    Article  PubMed  CAS  Google Scholar 

  • Hsu JY, Sun ZW, Li X, Reuben M, Tatchell K, Bishop DK, Grushcow JM, Brame CJ, Caldwell JA, Hunt DF, Lin R, Smith MM, Allis CD (2000) Mitotic phosphorylation of histone H3 is governed by Ipl1/aurora kinase and Glc7/PP1 phosphatase in budding yeast and nematodes. Cell 102:279–291

    Article  PubMed  CAS  Google Scholar 

  • Jeng YM, Peng SY, Lin CY, Hsu HC (2004) Over-expression and amplification of Aurora-A in hepatocellular carcinoma. Clin Cancer Res 10: 2065–2071

    Article  PubMed  CAS  Google Scholar 

  • Jiang N, Wang X, Yang Y, Dai W (2006) Advances in mitotic inhibitors for cancer treatment. Mini Rev Med Chem 6:885–895

    Article  PubMed  CAS  Google Scholar 

  • Jones SF, Cohen RB, Dees EC, Lee Y, Papas JA, Cooper MR, Galvin KM, Burris HA (2007) Phase I clinical trial of MLN8054, a selective inhibitor of aurora A kinase. Proc Am Soc Clin Oncol Annu Meet 25:3577

    Google Scholar 

  • Ju H, Cho H, Kim YS, Kim WH, Ihm C, Noh SM, Kim JB, Hahn DS, Choi BY, Kang C (2006) Functional polymorphism 57 Val>Ile of aurora kinase A associated with increased risk of gastric cancer progression. Cancer Lett 242: 273–279

    Article  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Keen N, Taylor S (2009) Mitotic drivers-inhibitors of the Aurora B Kinase. Cancer Metastasis Rev 28: 185–195

    Google Scholar 

  • Kimura M, Matsuda Y, Yoshioka T, Okano Y (1999) Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl 1-related protein kinase, AIK3. J Biol Chem 274:7334–7340

    Article  PubMed  CAS  Google Scholar 

  • Kimura M, Matsuda Y, Yoshioka T, Sumi N, Okano Y (1998) Identification and characterization of STK12/Aik2: a human gene related to aurora of Drosophila and yeast IPL1. Cytogenet Cell Genet 82:147–152

    Article  PubMed  CAS  Google Scholar 

  • Kimura MT, Mori T, Conroy J, Nowak NJ, Satomi S, Tamai K, Nagase H (2005) Two functional coding single nucleotide polymorphisms in STK15 (aurora-A) coordinately increase esophageal cancer risk. Cancer Res 65:3548–3554

    Article  PubMed  CAS  Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396: 643–649

    Article  PubMed  CAS  Google Scholar 

  • Li D, Zhu J, Firozi PF, Abbruzzese JL, Evans DB, Cleary K, Friess H, Sen S (2003) Over-expression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin Cancer Res 9: 991–997

    PubMed  CAS  Google Scholar 

  • Littlepage LE, Wu H, Andresson T, Deanehan JK, Amundadottir LT, Ruderman JV (2002) Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A. Proc Natl Acad Sci USA 99:15440–15445

    Article  PubMed  CAS  Google Scholar 

  • Lugo TG, Pendergast AM, Muller AJ, Witte ON (1990) Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 247:1079–1082

    Article  PubMed  CAS  Google Scholar 

  • Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, Galvin KM, Hoar KM, Huck JJ, Leroy PJ, Ray ET, Sells TB, Stringer B, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Bolen JB, Claiborne CF (2007) Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora-A kinase. Proc Natl Acad Sci USA 104:4106–4111

    Article  PubMed  CAS  Google Scholar 

  • Marumoto T, Hirota T, Morisaki T, Kunitoku N, Zhang D, Ichikawa Y, Sasayama T, Kuninaka S, Mimori T, Tamaki N, Kimura M, Okano Y, Saya H (2002) G2 checkpoint in mammalian cells. Genes Cells 7:1173–1182

    Article  PubMed  CAS  Google Scholar 

  • Meraldi P, Honda R, Nigg EA (2002) Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53 -/- cells. EMBO J 21:483–492

    Article  PubMed  CAS  Google Scholar 

  • Miao X, Sun T, Wang Y, Zhang X, Tan W, Lin D (2004) Functional STK15 Phe31Ile polymorphism is associated with the occurrence and advanced disease status of esophageal squamous cell carcinoma. Cancer Res 64:2680–2683

    Article  PubMed  CAS  Google Scholar 

  • Modugno M, Casale E, Soncini C, Rosettani P, Colombo R, Lupi R, Rusconi L, Fancelli D, Carpinelli P, Cameron AD, Isacchi A, Moll J (2007) Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor Danusertib. Cancer Res 67:7987–7990

    Article  PubMed  CAS  Google Scholar 

  • Monier K, Mouradian S, Sullivan KF (2007) DNA methylation promotes aurora-B -driven phosphorylation of histone H3 in chromosomal subdomains. J Cell Sci 120:101–114

    Article  PubMed  CAS  Google Scholar 

  • Neben K, Korshunov A, Benner A, Wrobel G, Hahn M, Kokocinski F, Golanov A, Joos S, Lichter P (2004) Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival. Cancer Res 64:3103–3111

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Ohi R, Sapra T, Howard J, Mitchison TJ (2004) Differentiation of cytoplasmatic and meiotic spindle assembly MCAK functions by Aurora B-dependent phosphorylation. Mol Biol Cell 15: 2895–2906

    Article  PubMed  CAS  Google Scholar 

  • Ota T, Suto S, Katayama H, Han ZB, Suzuki F, Maeda M, Tanino M, Terada Y, Tatsuka M (2002) Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res 62:5168–5177

    PubMed  CAS  Google Scholar 

  • Paquette R, Shah NP, Sawyers CL, Martinelli G, John N, Chalukya M, Rocchetti M, Fiocchi C, Comis S, Capolongo L, Laffranchi B (2007) Danusertib , an Aurora kinase inhibitor, induces clinical responses in chronic myeloid leukemia harboring T315I mutations of BCR-ABL. Blood 110:abstr. 1030

    Google Scholar 

  • Propp S, Lizzi FA (1970) Philadelphia chromosome in acute lymhocytic leukemia. Blood 36: 353–360

    PubMed  CAS  Google Scholar 

  • Ravandi F, Foran J, Verstovsek S, Cortes J, Wierda W, Boone P, Borthakur G, Sweeney T, Kantarjian H (2007) A phase I trial of AT9283, a multitargeted kinase inhibitor, in patients with refractory hematological malignancies. Blood 110:abstr. 904

    Google Scholar 

  • Rubin EH, Shapiro GI, Stein MN, Watson P, Bergstrom D, Xiao A, Clark JB, Freedman SJ, Eder JP (2006) A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients. J Clin Oncol 24:abstr. 3009

    Google Scholar 

  • Sasai K, Katayama H, Stenoien DL, Fujii S, Honda R, Kimura M, Okano Y, Tatsuka M, Suzuki F, Nigg EA, Earnshaw WC, Brinkley WR, Sen S (2004) Aurora C kinase is a novel chromosomal passenger protein that can complement Aurora B kinase function in mitotic cells. Cell Motil Cyto­skeleton 59:249–263

    Article  PubMed  CAS  Google Scholar 

  • Schellens JH, Boss D, Witteveen PO, Zandvliet A, Beijnen JH, Voogel-Fuchs M, Morris C, Wilson D, Voest EE (2006) Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152. J Clin Oncol 24(20 Suppl):3008

    Google Scholar 

  • Schmidt M, Bastians H (2007) Mitotic drug targets and the development of novel anti-mitotic anticancer drugs. Drug Resist Updat 10:162–181

    Article  PubMed  CAS  Google Scholar 

  • Sen S, Zhou H, White RA (1997) A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene 14: 2195–2200

    Article  PubMed  CAS  Google Scholar 

  • Sen S, Zhou H, Zhang RD, Yoon DS, Vakar-Lopez F, Ito S, Jiang F, Johnston D, Grossman HB, Ruifrok AC, Katz RL, Brinkley W, Czerniak B (2002) Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 94:1320–1329

    PubMed  CAS  Google Scholar 

  • Shah NP, Kasap C, Paquette R, Cortes J, Pinilla J, Talpaz M, Bui LA, Clary DO (2007) Targeting drug-resistant CML and Ph+ ALL with the spectrum selective protein kinase inhibitor XL228. Blood 110:abstr. 474

    Google Scholar 

  • Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farell C, Meeh P, Markowitz SD, Willis J, dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274

    Article  PubMed  CAS  Google Scholar 

  • Smith SL, Bowers NL, Betticher DC, Gautschi O, Ratschiller D, Hoban PR, Booton R, Santibanez-Koref MF, Heighway J (2005) Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability. Br J Cancer 93: 719–729

    Article  PubMed  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • Steeghs N, Eskens F, Gelderblom H, Verweij J, Nortier J, Ouwerkerk J, van Noort C, Mariani M, Spinelli R, Carpinelli P, Laffranchi B, de Jonge M (2009) A Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor PHA-739358 in Patients with Advanced or Metastatic Solid Tumors. J Clin Oncol; in press

    Google Scholar 

  • Takahashi T, Futamura M, Yoshimi N, Sano J, Katada M, Takagi Y, Kimura M, Yoshioka T, Okano Y, Saji S (2000) Centrosomal kinases, HsAIRK1 and HsAIRK3, are overexpressed in primary colorectal cancers. Jpn J Cancer Res 91: 1007–1014

    PubMed  CAS  Google Scholar 

  • Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y (1999) Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res 59:2041–2044

    PubMed  CAS  Google Scholar 

  • Tanner MM, Grenman S, Koul A, Johannsson O, Meltzer P, Pejovic T, Borg A, Isola JJ (2000) Frequent amplification of chromosomal region 20q12–q13 in ovarian cancer. Clin Cancer Res 6: 1833–1839

    PubMed  CAS  Google Scholar 

  • Tatsuka M, Katayama H, Ota T, Tanaka T, Odashima S, Suzuki F, Terada Y (1998) Multinuclearity and increased ploidy caused by overexpression of the aurora- and lpl1-like midbody-associated protein kinase in human cancer cells. Cancer Res 58:4811–4816

    PubMed  CAS  Google Scholar 

  • Tsai MY, Wiese C, Cao K, Martin O, Donovan P, Ruderman J, Prigent C, Zheng Y (2003) A Ran signalling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nat Cell Biol 5:242–248

    Article  PubMed  CAS  Google Scholar 

  • Vader G, Medema RH, Lens SM (2006) The chromosomal passenger complex: guiding aurora-B through mitosis. J Cell Biol 173:833–837

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Zhou YX, Qiao W, Tominaga Y, Ouchi M, Ouchi T, Deng CX (2006) Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation. Oncogene 25: 7148–7158

    Article  PubMed  CAS  Google Scholar 

  • Warner SL, Bearss DJ, Han H, Von Hoff DD (2003) Targeting Aurora-2 kinase in cancer. Mol Cancer Ther 2:589–595

    PubMed  CAS  Google Scholar 

  • Young MA, Shah NP, Chao LH, Seeliger M, Milanov ZV, Biggs WH III, Treiber DK, Patel HK, Zarrinkar PP, Lockhart DJ, Sawyers CL, Kuriyan J (2006) Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680. Cancer Res 66:1007–1014

    Article  PubMed  CAS  Google Scholar 

  • Zeitlin SG, Shelby RD, Sullivan KF (2001) CENP-A is phosphorylated by Aurora B kinase and plays an unexpected role in completion of cytokinesis. J Cell Biol 155:1147–1157

    Article  PubMed  CAS  Google Scholar 

  • Zhang W (2006) Inhibition of the drug-resistant T315I mutant of BCR-ABL. Eur J Cancer Suppl 4:54

    Article  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We thank Jürgen Moll from Nerviano Medical Sciences for critical reading of the manuscript.

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Authors and Affiliations

  1. Dept. of Hematology and Oncology, University Hospital Aachen, Pauwelsstraße 30, 52074, Aachen, Germany

    Tim H. Brümmendorf

  2. University Cancer Center Hamburg (UCCH), University Hospital Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

    Tim H. Brümmendorf

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  2. Tim H. Brümmendorf
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Correspondence to Tim H. Brümmendorf .

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  1. Medizinische Klinik III, SLK-Kliniken Heilbronn GmbH, Am Gesundbrunen 20-26, Heilbronn, 74078, Germany

    Uwe M. Martens

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Gontarewicz, A., Brümmendorf, T.H. (2010). Danusertib (formerly PHA-739358) – A Novel Combined Pan-Aurora Kinases and Third Generation Bcr-Abl Tyrosine Kinase Inhibitor. In: Martens, U. (eds) Small Molecules in Oncology. Recent Results in Cancer Research, vol 184. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-01222-8_14

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  • DOI: https://doi.org/10.1007/978-3-642-01222-8_14

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