Phthalazinone Pyrazoles as Potent, Selective, and Orally Bioavailable Inhibitors of Aurora-A Kinase

被引：79
作者：
Prime, Michael E. [1 ]
Courtney, Stephen M. [1 ]
Brookfield, Frederick A. [1 ]
Marston, Richard W. [1 ]
Walker, Victoria [1 ]
Warne, Justin [1 ]
Boyd, Andrew E.
Kairies, Norman A. [3 ]
von der Saal, Wolfgang [2 ]
Limberg, Anja [2 ]
Georges, Guy [2 ]
Engh, Richard A. [3 ]
Goller, Bernhard [2 ]
Rueger, Petra [2 ]
Rueth, Matthias [2 ]
机构：
[1] Evotec UK Ltd, Abingdon OX14 4SA, Oxon, England
[2] Roche Diagnost GmbH, Pharma Res Penzberg, D-82372 Penzberg, Germany
[3] Max Planck Inst Biochem, D-82152 Planegg Martinsried, Germany
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 01期
关键词：
AURORA/IP11-RELATED PROTEIN-KINASE; SMALL-MOLECULE INHIBITOR; IN-VIVO; ANTICANCER AGENTS; B KINASE; SPINDLE; CELLS; CYTOKINESIS; CHECKPOINT; DISCOVERY;
D O I：
10.1021/jm101346r
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scoff old The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically > 1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680
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页码：312 / 319
页数：8
相关论文
共 24 条
  • [1] Discovery of GSK1070916, a Potent and Selective Inhibitor of Aurora B/C Kinase
    Adams, Nicholas D.
    Adams, Jerry L.
    Burgess, Joelle L.
    Chaudhari, Amita M.
    Copeland, Robert A.
    Donatelli, Carla A.
    Drewry, David H.
    Fisher, Kelly E.
    Hamajima, Toshihiro
    Hardwicke, Mary Ann
    Huffman, William F.
    Koretke-Brown, Kristin K.
    Lai, Zhihong V.
    McDonald, Octerloney B.
    Nakamura, Hiroko
    Newlander, Ken A.
    Oleykowski, Catherine A.
    Parrish, Cynthia A.
    Patrick, Denis R.
    Plant, Ramona
    Sarpong, Martha A.
    Sasaki, Kosuke
    Schmidt, Stanley J.
    Silva, Domingos J.
    Sutton, David
    Tang, Jun
    Thompson, Christine S.
    Tummino, Peter J.
    Wang, Jamin C.
    Xiang, Hong
    Yang, Jingsong
    Dhanak, Dashyant
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2010, 53 (10) : 3973 - 4001
  • [2] Aurora-A: the maker and breaker of spindle poles
    Barr, Alexis R.
    Gergely, Fanni
    [J]. JOURNAL OF CELL SCIENCE, 2007, 120 (17) : 2987 - 2996
  • [3] Structural basis of Aurora-A activation by TPX2 at the mitotic spindle
    Bayliss, R
    Sardon, T
    Vernos, I
    Conti, E
    [J]. MOLECULAR CELL, 2003, 12 (04) : 851 - 862
  • [4] Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores
    Ditchfield, C
    Johnson, VL
    Tighe, A
    Ellston, R
    Haworth, C
    Johnson, T
    Mortlock, A
    Keen, N
    Taylor, SS
    [J]. JOURNAL OF CELL BIOLOGY, 2003, 161 (02) : 267 - 280
  • [5] On the role of aurora-A in centrosome function
    Dutertre, S
    Descamps, S
    Prigent, C
    [J]. ONCOGENE, 2002, 21 (40) : 6175 - 6183
  • [6] Aurora A kinase RNAi and small molecule inhibition of Aurora kinases with VE-465 induce apoptotic death in multiple myeloma cells
    Evans, Robert
    Naber, Claudia
    Steffler, Tara
    Checkland, Tamara
    Keats, Jonathan
    Maxwell, Christopher
    Perry, Troy
    Chau, Heidi
    Belch, Andrew
    Pilarski, Linda
    Reiman, Tony
    [J]. LEUKEMIA & LYMPHOMA, 2008, 49 (03) : 559 - 569
  • [7] MUTATIONS IN AURORA PREVENT CENTROSOME SEPARATION LEADING TO THE FORMATION OF MONOPOLAR SPINDLES
    GLOVER, DM
    LEIBOWITZ, MH
    MCLEAN, DA
    PARRY, H
    [J]. CELL, 1995, 81 (01) : 95 - 105
  • [8] VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo
    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, JMC
    Miller, KM
    [J]. NATURE MEDICINE, 2004, 10 (03) : 262 - 267
  • [9] The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint
    Hauf, S
    Cole, RW
    LaTerra, S
    Zimmer, C
    Schnapp, G
    Walter, R
    Heckel, A
    van Meel, J
    Rieder, CL
    Peters, JM
    [J]. JOURNAL OF CELL BIOLOGY, 2003, 161 (02) : 281 - 294
  • [10] A quantitative analysis of kinase inhibitor selectivity
    Karaman, Mazen W.
    Herrgard, Sanna
    Treiber, Daniel K.
    Gallant, Paul
    Atteridge, Corey E.
    Campbell, Brian T.
    Chan, Katrina W.
    Ciceri, Pietro
    Davis, Mindy I.
    Edeen, Philip T.
    Faraoni, Raffaella
    Floyd, Mark
    Hunt, Jeremy P.
    Lockhart, Daniel J.
    Milanov, Zdravko V.
    Morrison, Michael J.
    Pallares, Gabriel
    Patel, Hitesh K.
    Pritchard, Stephanie
    Wodicka, Lisa M.
    Zarrinkar, Patrick P.
    [J]. NATURE BIOTECHNOLOGY, 2008, 26 (01) : 127 - 132
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