Aurora kinase inhibitors: Current status and outlook

Frontiers in Oncology

Volumn 5, Issue DEC, 2015, Pages

  Bavetsias, Vassilios ^a   Linardopoulos, Spiros ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

Aurora kinase; Hematologic diseases; Kinase inhibitors; Neuroblastoma; Small molecules

Indexed keywords

1 CYCLOPROPYL 3 [3 (5 MORPHOLINOMETHYL 1H BENZIMIDAZOL 2 YL) 1H PYRAZOL 4 YL]UREA; ALISERTIB; AMG 900; AURORA A KINASE; AURORA B KINASE; AURORA C KINASE; AURORA KINASE INHIBITOR; BARASERTIB; DANUSERTIB; PF 3814735; TEMOZOLOMIDE; UNCLASSIFIED DRUG;

ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE MYELOBLASTIC LEUKEMIA; CELL CYCLE REGULATION; CHROMOSOME SEGREGATION; CYTOKINESIS; DNA DAMAGE; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; EWING SARCOMA; HEMATOLOGIC MALIGNANCY; HISTOPATHOLOGY; HUMAN; MITOSIS; NEUROBLASTOMA; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROTEIN EXPRESSION; REVIEW; TUMOR GROWTH;

EID: 84954551780     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2015.00278     Document Type: Review

References (91)

1. BischoffJR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J (1998) 17:3052-65. doi: 10.1093/emboj/17.11.3052.
2. Carmena M, Earnshaw WC. The cellular geography of aurora kinases. Nat Rev Mol Cell Biol (2003) 4:842-54. doi:10.1038/nrm1245.
3. Giet R, Prigent C. Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. J Cell Sci (1999) 112:3591-601.
4. Girdler F, Gascoigne KE, Eyers PA, Hartmuth S, Crafter C, Foote KM, et al. Validating aurora B as an anti-cancer drug target. J Cell Sci (2006) 119:3664-75. doi:10.1242/jcs.03145.
5. Carpinelli P, Moll J. Aurora kinase inhibitors: identification and preclinical validation of their biomarkers. Expert Opin Ther Targets (2008) 12:69-80. doi:10.1517/14728222.12.1.69.
6. Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN Jr, Gandara DR. Aurora kinases as anticancer drug targets. Clin Cancer Res (2008) 14:1639-48. doi:10.1158/1078-0432.CCR-07-2179.
7. Vader G, Medema RH, Lens SM. The chromosomal passenger complex: guiding aurora-B through mitosis. J Cell Biol (2006) 173:833-7. doi:10.1083/jcb.200604032.
8. Sampath SC, Ohi R, Leismann O, Salic A, Pozniakovski A, Funabiki H. The chromosomal passenger complex is required for chromatin-induced microtubule stabilization and spindle assembly. Cell (2004) 118:187-202. doi:10.1016/j.cell.2004.06.026.
9. Terada Y, Tatsuka M, Suzuki F, Yasuda Y, Fujita S, Otsu M. AIM-1: a mammalian midbody-associated protein required for cytokinesis. EMBO J (1998) 17:667-76. doi:10.1093/emboj/17.3.667.
10. Carmena M, Wheelock M, Funabiki H, Earnshaw WC. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat Rev Mol Cell Biol (2012) 13:789-803. doi:10.1038/nrm3474.
11. Tanenbaum ME, Macurek L, van der Vaart B, Galli M, Akhmanova A, Medema RH. A complex of Kif18b and MCAK promotes microtubule depolymerization and is negatively regulated by aurora kinases. Curr Biol (2011) 21:1356-65. doi:10.1016/j.cub.2011.07.017.
12. Ulisse S, Delcros JG, Baldini E, Toller M, Curcio F, Giacomelli L, et al. Expression of aurora kinases in human thyroid carcinoma cell lines and tissues. Int J Cancer (2006) 119:275-82. doi:10.1002/ijc.21842.
13. Bernard M, Sanseau P, Henry C, Couturier A, Prigent C. Cloning of STK13, a third human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on chromosome 19q13.3-ter. Genomics (1998) 53:406-9. doi:10.1006/geno.1998.5522.
14. Kimura M, Matsuda Y, Yoshioka T, Okano Y. Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem (1999) 274:7334-40. doi:10.1074/jbc.274.11.7334.
15. Yang KT, Li SK, Chang CC, Tang CJ, Lin YN, Lee SC, et al. Aurora-C kinase deficiency causes cytokinesis failure in meiosis-I and production of large polyploid oocytes in mouse. Mol Biol Cell (2010) 21:2371-83. doi:10.1091/mbc. E10-02-0170.
16. Khan J, Ezan F, Crémet JY, Fautrel A, Gilot D, Lambert M, et al. Overexpression of active aurora-C kinase results in cell transformation and tumour formation. PLoS One (2011) 6:e26512. doi:10.1371/journal.pone.0026512.
17. Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, et al. Tumor amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet (1998) 20:189-93. doi:10.1038/2496.
18. Gritsko TM, Coppola D, Paciga JE, Yang L, Sun M, Shelley SA, et al. Activation and overexpression of centrosome kinase BTAK/aurora-A in human ovarian cancer. Clin Cancer Res (2003) 9:1420-6.
19. Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y. Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res (1999) 59:2041-4.
20. Reichardt W, Jung V, Brunner C, Klein A, Wemmert S, Romeike BF, et al. The putative serine/threonine kinase gene STK15 on chromosome 20q13.2 is amplified in human gliomas. Oncol Rep (2003) 10:1275-9.
21. Araki K, Nozaki K, Ueba T, Tatsuka M, Hashimoto N. High expression of aurora-B/aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas. J Neurooncol (2004) 67:53-64. doi:10.1023/B:NEON.0000021784.33421.05.
22. ChieffiP, Troncone G, Caleo A, Libertini S, Linardopoulos S, Tramontano D, et al. Aurora B expression in normal testis and seminomas. J Endocrinol (2004) 181:263-70. doi:10.1677/joe.0.1810263.
23. Sorrentino R, Libertini S, Pallante PL, Troncone G, Palombini L, Bavetsias V, et al. Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab (2005) 90:928-35. doi:10.1210/jc.2004-1518.
24. Giet R, Petretti C, Prigent C. Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol (2005) 15:241-50. doi:10.1016/j.tcb.2005.03.004.
25. 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) 8:2046-56. doi:10.1158/1535-7163.MCT-09-0323.
26. Otto T, Horn S, Brockmann M, Eilers U, Schüttrumpf L, Popov N, et al. Stabilization of N-Myc is a critical function of aurora A in human neuroblastoma. Cancer Cell (2009) 15:67-78. doi:10.1016/j.ccr.2008.12.005.
27. Gustafson WC, Meyerowitz JG, Nekritz EA, Chen J, Benes C, Charron E, et al. Drugging MYCN through an allosteric transition in aurora kinase A. Cancer Cell (2014) 26:414-27. doi:10.1016/j.ccr.2014.07.015.
28. Mortlock AA, Foote KM, Heron NM, Jung FH, Pasquet G, Lohmann J-JM, et al. Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase. J Med Chem (2007) 50:2213-24. doi:10.1021/jm061335f.
29. Dennis M, Davies M, Oliver S, D'Souza R, Pike L, Stockman P. Phase I study of the aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia. Cancer Chemother Pharmacol (2012) 70:461-9. doi:10.1007/s00280-012-1939-2.
30. Boss DS, Witteveen PO, van der Sar J, Lolkema MP, Voest EE, Stockman PK, et al. Clinical evaluation of AZD1152, an i.v. inhibitor of aurora B kinase, in patients with solid malignant tumors. Ann Oncol (2011) 22:431-7. doi:10.1093/annonc/mdq344.
31. Schwartz GK, Carvajal RD, Midgley R, Rodig SJ, Stockman PK, Ataman O, et al. Phase I study of barasertib (AZD1152), a selective inhibitor of aurora B kinase, in patients with advanced solid tumors. Invest New Drugs (2013) 31:370-80. doi:10.1007/s10637-012-9825-7.
32. Lowenberg B, Muus P, Ossenkoppele G, Rousselot P, Cahn J-Y, Ifrah N, et al. Phase1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced myeloid leukemia. Blood (2011) 118:6030-6. doi:10.1182/blood-2011-07-366930.
33. Tsuboi K, Yokozawa T, Sakura T, Watanabe T, Fujisawa S, Yamauchi T, et al. A phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia. Leuk Res (2011) 35:1384-9. doi:10.1016/j.leukres.2011.04.008.
34. Kantarjian HM, Sekeres MA, Ribrag V, Rousselot P, Garcia-Manero G, Jabbour EJ, et al. Phase I study assessing the safety and tolerability of barasertib (AZD1152) with low-dose cytosine arabinoside in elderly patients with AML. Clin Lymphoma Myeloma Leuk (2013) 13:559-67. doi:10.1016/j.clml.2013.03.019.
35. Kantarjian HM, Martinelli G, Jabbour EJ, Quintas-Cardama A, Ando K, Bay J-O, et al. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer (2013) 119(14):2611-9. doi:10.1002/cncr.28113.
36. Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM, et al. Characterisation of alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res (2011) 17:7614-24. doi:10.1158/1078-0432.CCR-11-1536.
37. Sells TB, Chau R, Ecsedy JA, Gershman RE, Hoar K, Huck J, et al. MLN8054 and alisertib (MLN8237): discovery of selective oral aurora A inhibitors. ACS Med Chem Lett (2015) 6:630-4. doi:10.1021/ml500409n.
38. Carol H, Boehm I, Reynolds CP, Kang MH, Maris JM, Morton CL, et al. Efficacy and pharmacokinetic/pharmacodynamics evaluation of the aurora kinase inhibitor MLN8237 against preclinical models of pediatric cancer. Cancer Chemother Pharmacol (2011) 68:1291-304. doi:10.1007/s00280-011-1618-8.
39. Kelly KR, Nawrocki ST, Espitia CM, Zhang M, Yang JJ, Padmanabhan S, et al. Targeting aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism. Int J Cancer (2012) 131:2693-703. doi:10.1002/ijc.27579.
40. Kelly KR, Ecsedy J, Medina E, Mahalingam D, Padmanabhan S, Nawrocki ST, et al. The novel aurora A kinase inhibitor MLN8237 is active in resistant chronic myeloid leukemia and significantly increases the efficacy of nilotinib. J Cell Mol Med (2011) 15:2057-70. doi:10.1111/j.1582-4934.2010.01218.x.
41. Dees EC, Cohen RB, von Mehren M, Stinchcombe TE, Liu H, Venkatakrishnan K, et al. Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res (2012) 18:4775-84. doi:10.1158/1078-0432.CCR-12-0589.
42. Cervantes A, Elez E, Roda D, Ecsedy J, Macarulla T, Venkatakrishnan K, et al. Phase I pharmacokinetic/pharmacodynamics study of MLN8237, an investigational, oral, selective aurora A kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res (2012) 18:4764-74. doi:10.1158/1078-0432.CCR-12-0571.
43. Matulonis UA, Sharma S, Ghamande S, Gordon MS, Del Prete SA, Ray-Coquard I, et al. Phase II study of MLN8237 (alisertib), an investigational aurora A kinase inhibitor, in patients with platinum-resistant or-refractory epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Gynecol Oncol (2012) 127:63-9. doi:10.1016/j.ygyno.2012.06.040.
44. Mosse YP, Lipsitz E, Fox E, Teachey DT, Maris JM, Weigel B, et al. Pediatric phase I trial and pharmacokinetic study of MLN8237, an investigational oral selective small-molecule inhibitor of aurora kinase A: a children's oncology group phase I consortium study. Clin Cancer Res (2012) 18:6058-64. doi:10.1158/1078-0432.CCR-11-3251.
45. Kelly KR, Shea TC, Goy A, Berdeja JG, Reeder CB, McDonagh KT, et al. Phase I study of MLN8237-investigational aurora A kinase inhibitor-in relapsed/refractory multiple myeloma, non-Hodgkin lymphoma and chronic lymphocytic leukemia. Invest New Drugs (2014) 32:489-99. doi:10.1007/s10637-013-0050-9.
46. Friedberg JW, Mahadevan D, Cebula E, Persky D, Lossos I, Agarwal AB, et al. Phase II study of alisertib, a selective aurora A kinase inhibitor, in relapsed and refractory aggressive B-and T-cell Non-Hodgkin lymphomas. J Clin Oncol (2014) 32:44-50. doi:10.1200/JCO.2012.46.8793.
47. Goldberg SL, Fenaux P, Craig MD, Gyan E, Lister J, Kassis J, et al. An exploratory phase 2 study of investigational aurora A kinase inhibitor alisertib (MLN8237) in acute myelogenous leukemia and myelodysplastic syndromes. Leuk Res Rep (2014) 3:58-61. doi:10.1016/j.lrr.2014.06.003.
48. Fancelli D, Moll J, Varasi M, Bravo R, Artico R, Berta D, et al. 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem (2006) 49:7247-51. doi:10.1021/jm060897w.
49. Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, et al. PHA-739358, a potent inhibitor of aurora kinases with a selective target inhibition profile relevant to cancer. Mol Cancer Ther (2007) 6:3158-68. doi:10.1158/1535-7163.MCT-07-0444.
50. Modugno M, Casale E, Soncini C, Rosettani P, Colombo R, Lupi R, et al. Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358. Cancer Res (2007) 67:7987-90. doi:10.1158/0008-5472.CAN-07-1825.
51. Steeghs N, Eskens FALM, Gelderblom H, Verweij J, Nortier JWR, Ouwerkerk J, et al. Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors. J Clin Oncol (2009) 27:5094-101. doi:10.1200/JCO.2008.21.6655.
52. Schoffski P, Besse B, Gauler T, de Jonge MJA, Scambia G, Santoro A, et al. Efficacy and safety of biweekly i.v. administrations of the aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumor, multi-institutional phase II study. Ann Oncol (2015) 26:598-607. doi:10.1093/annonc/mdu566.
53. Meulenbeld HJ, Bleuse JP, Vinci EM, Raymond E, Vitali G, Santoro A, et al. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU Int (2013) 111:44-52. doi:10.1111/j.1464-410X.2012.11404.x.
54. Cohen RB, Jones SF, Aggarwal C, von Mehren M, Cheng J, Spigel DR, et al. A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clin Cancer Res (2009) 15:6694-701. doi:10.1158/1078-0432.CCR-09-1445.
55. Paquette R, Shah N, Sawyers C, Martinelli G, Nicoll J, Chalukya M, et al. Pha-739358: a pan-aurora kinase inhibitor. Hematol Meet Rep (2008) 2:92-3.
56. Borthakur G, Dombret H, Schafhausen P, Brummendorf TH, Boissel N, Jabbour E, et al. A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy. Haematologica (2015) 100:898-904. doi:10.3324/haematol.2014.115279.
57. Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, et al. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem (2009) 52:379-88. doi:10.1021/jm800984v.
58. Tanaka R, Squires MS, Kimura S, Yokota A, Nagao R, Yamauchi T, et al. Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells. Blood (2010) 116:2089-95. doi:10.1182/blood-2009-03-211466.
59. Curry J, Angove H, Fazal L, Lyons J, Reule M, Thompson N, et al. Aurora B kinase inhibition in mitosis, strategies for optimising the use of aurora kinase inhibitors such as AT9283. Cell Cycle (2009) 8:1921-9. doi:10.4161/cc.8.12.8741.
60. Qi W, Liu X, Cooke LS, Persky DO, Miller TP, Squires M, et al. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer (2012) 130:2997-3005. doi:10.1002/ijc.26324.
61. Arkenau H-T, Plummer R, Molife LR, Olmos D, Yap TA, Squires M, et al. A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies. Ann Oncol (2012) 23:1307-13. doi:10.1093/annonc/mdr451.
62. Dent SF, Gelmon KA, Chi KN, Jonker DJ, Wainman N, Capier CA, et al. NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies. Invest New Drugs (2013) 31:1522-9. doi:10.1007/s10637-013-0018-9.
63. Moreno L, Marshall LV, Pearson ADJ, Morland B, Elliott M, Campbell-Hewson Q, et al. A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a cancer research UK study. Clin Cancer Res (2015) 21:267-73. doi:10.1158/1078-0432.CCR-14-1592.
64. Foran J, Ravandi F, Wierda W, Garcia-Manero G, Verstovsek S, Kadia T, et al. A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis. Clin Lymphoma Myeloma Leuk (2014) 14:223-30. doi:10.1016/j.clml.2013.11.001.
65. Jani JP, Arcari J, Bernardo V, Bhattacharya SK, Briere D, Cohen BD, et al. PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy. Mol Cancer Ther (2010) 9:883-94. doi:10.1158/1535-7163.MCT-09-0915.
66. Schoffski P, Jones SF, Dumez H, Infante JR, Mieghem EV, Fowst C, et al. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumors. Eur J Cancer (2011) 47:2256-64. doi:10.1016/j.ejca.2011.07.008.
67. Payton M, Bush TL, Chung G, Ziegler B, Eden P, McElroy P, et al. Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. Cancer Res (2010) 70:9846-54. doi:10.1158/0008-5472.CAN-10-3001.
68. Geuns-Meyer S, Cee VJ, Deak HL, Du B, Hodous BL, Nguyen HN, et al. Discovery of N-(4-(3-(2-aminopyrimidin-4-yl)pyridine-2-yloxy)phenyl)-4-(4-methylthiophen-2-yl)phthalazin-1-amine (AMG 900), a highly selective, orally bioavailable inhibitor of aurora kinases with activity against multidrug-resistant cell lines. J Med Chem (2015) 58:5189-207. doi:10.1021/acs.jmedchem.5b00183.
69. Linardopoulos S, Blagg J. Aurora kinase inhibition: a new light in the sky? J Med Chem (2015) 58:5186-8. doi:10.1021/acs.jmedchem.5b00918.
70. Bush TL, Payton M, Heller S, Chung G, Hanestad K, Rottman JB, et al. AMG 900, a small-molecule inhibitor of aurora kinases, potentiates the activity of microtubule-targeting agents in human metastatic breast cancer models. Mol Cancer Ther (2013) 12:2356-66. doi:10.1158/1535-7163.MCT-12-1178.
71. Moore AS, Blagg J, Linardopoulos S, Pearson AD. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias. Leukemia (2010) 24:671-8. doi:10.1038/leu.2010.15.
72. Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y, et al. 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) 110:2034-40. doi:10.1182/blood-2007-02-073700.
73. 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) 93:662-9. doi:10.3324/haematol.12148.
74. Oke A, Pearce D, Wilkinson RW, Crafter C, Odedra R, Cavenagh J, et al. AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res (2009) 69:4150-8. doi:10.1158/0008-5472.CAN-08-3203.
75. Grundy M, Seedhouse C, Shang S, Richardson J, Russell N, Pallis M. The FLT3 internal tandem duplication mutation is a secondary target of the aurora B kinase inhibitor AZD1152-HQPA in acute myelogenous leukemia cells. Mol Cancer Ther (2010) 9:661-72. doi:10.1158/1535-7163.MCT-09-1144.
76. Knapper S. The clinical development of FLT3 inhibitors in acute myeloid leukemia. Expert Opin Investig Drugs (2011) 20:1377-95. doi:10.1517/13543784.2011.611802.
77. Levis MJ. Will newer tyrosine kinase inhibitors have an impact in AML? Best Pract Res Clin Haematol (2010) 23:489-94. doi:10.1016/j.beha.2010.09.008.
78. Moore AS, Faisal A, Gonzalez de Castro D, Bavetsias V, Sun C, Atrash B, et al. Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. Leukemia (2012) 26:1462-70. doi:10.1038/leu.2012.52.
79. Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, et al. Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia. J Med Chem (2012) 55:8721-34. doi:10.1021/jm300952s.
80. Grimmer MR, Weiss WA. Childhood tumors of the nervous system as disorders of normal development. Curr Opin Pediatr (2006) 18:634-8. doi:10.1097/MOP.0b013e32801080fe.
81. Burkhart CA, Cheng AJ, Madafiglio J, Kavallaris M, Mili M, Marshall GM, et al. Effects of MYCN antisense oligonucleotide administration on tumorigenesis in a murine model of neuroblastoma. J Natl Cancer Inst (2003) 95:1394-403. doi:10.1093/jnci/djg045.
82. Chesler L, Schlieve C, Goldenberg DD, Kenney A, Kim G, McMillan A, et al. Inhibition of phosphatidylinositol 3-kinase destabilizes Mycn protein and blocks malignant progression in neuroblastoma. Cancer Res (2006) 66:8139-46. doi:10.1158/0008-5472.CAN-05-2769.
83. Faisal A, Vaughan L, Bavetsias V, Sun C, Atrash B, Avery S, et al. The aurora kinase inhibitor CCT137690 downregulates MYCN and sensitizes MYCN-amplified neuroblastoma in vivo. Mol Cancer Ther (2011) 10:2115-23. doi:10.1158/1535-7163.MCT-11-0333.
84. Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of aurora A kinase. Proc Natl Acad Sci U S A (2007) 104:4106-11. doi:10.1073/pnas.0608798104.
85. Cazales M, Schmitt E, Montembault E, Dozier C, Prigent C, Ducommun B. CDC25B phosphorylation by aurora-A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle (2005) 4:1233-8. doi:10.4161/cc.4.9.1964.
86. Krystyniak A, Garcia-Echeverria C, Prigent C, Ferrari S. Inhibition of aurora A in response to DNA damage. Oncogene (2006) 25:338-48.
87. Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature (2008) 455:119-23. doi:10.1038/nature07185.
88. Seki A, Coppinger JA, Jang CY, Yates JR, Fang G. Bora and the kinase aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science (2008) 320:1655-8. doi:10.1126/science.1157425.
89. Sourisseau T, Maniotis M, Tang C, Lord CJ, Ashworth A, Linardopoulos S. The mitotic kinase aurora-A suppresses homology-directed DNA double strand-break repair. EMBO Mol Med (2010) 2:130-42. doi:10.1002/emmm.201000068.
90. Tao Y, Leteur C, Calderaro J, Girdler F, Zhang P, Frascogna V, et al. The aurora B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe. Cell Cycle (2009) 8:3172-81. doi:10.4161/cc.8.19.9729.
91. Hong X, O'Donnell JP, Salazar CR, Van Brocklyn JR, Barnett KD, Pearl DK, et al. The selective aurora-A kinase inhibitor MLN8237 (alisertib) potently inhibits proliferation of glioblastoma neurosphere tumor stem-like cells and potentiates the effects of temozolomide and ionizing radiation. Cancer Chemother Pharmacol (2014) 73:983-90. doi:10.1007/s00280-014-2430-z.