Inhibition of Cdc25 phosphatases by indolyldihydroxyquinones

被引:66
|
作者
Sohn, J
Kiburz, B
Li, ZT
Deng, L
Safi, A
Pirrung, MC
Rudolph, J [1 ]
机构
[1] Duke Univ, Dept Biochem & Chem, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Durham, NC 27710 USA
关键词
D O I
10.1021/jm0300835
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Overexpression. of the Cdc25A and Cdc25B dual-specificity phosphatases correlates with a wide variety of cancers, making the Cdc25s attractive drug targets for anticancer therapies. However, the search for good lead molecules has been hampered by the reactivity of the active site thiolate anion and the flat solvent-exposed active site region. We describe here the indolyldihydrox-yquinones, a new class of inhibitors of Cdc25 that bind reversibly to the active site with submicromolar potency, Structure-activity relationships in the 50 derivatives of the lead molecule 2,5-dihydroxy-3-(1H-indol-3-yl)[1,4]benzoquinone show interesting and consistent trends identifying features required for inhibition of all three isoforms of Cdc25. The compounds do not show time-dependent inhibition, indicating that they form neither covalent adducts with nor oxidize the active site thiol. Our best compounds, 2,5-dihydroxy-3-(7-farnesyl-1H-indol-3-yl)[1,4]-benzoquinone and 2,5-dihydroxy-3-(4,6-dichloro-7-farnesyl-1H-indol-3-yl)[1,4]-benzoquinone, are competitive with substrate for the active site and yield K(i)s of 640 and 470 nM, respectively. Binding of the indolylhydroxyquinones is diminished by three, but not by six other, specific mutations in the active site region. Additionally, the flexible C-terminal tail required for binding of protein substrate is also required for binding derivatives with hydrophobic modifications at the 7-position. The indolyldihydroxyquinones compete effectively with the protein substrate for Cdc25 in vitro and lead to rapid cell death in vivo. Thus, the indolyldihydroxyquinones will serve as useful lead molecules for drug discovery and further cell-based studies on the role of Cdc25s in cell cycle control.
引用
收藏
页码:2580 / 2588
页数:9
相关论文
共 50 条
  • [1] Cdc25 phosphatases and cancer
    Kristjánsdóttir, K
    Rudolph, J
    CHEMISTRY & BIOLOGY, 2004, 11 (08): : 1043 - 1051
  • [2] Binding and inhibition of Cdc25 phosphatases by vitamin K analogues
    Kar, S
    Lefterov, IM
    Wang, MF
    Lazo, JS
    Scott, CN
    Wilcox, CS
    Carr, BI
    BIOCHEMISTRY, 2003, 42 (35) : 10490 - 10497
  • [3] The when and wheres of CDC25 phosphatases
    Boutros, R
    Dozier, C
    Ducommun, B
    CURRENT OPINION IN CELL BIOLOGY, 2006, 18 (02) : 185 - 191
  • [4] Redox regulation of the Cdc25 phosphatases
    Rudolph, J
    ANTIOXIDANTS & REDOX SIGNALING, 2005, 7 (5-6) : 761 - 767
  • [5] CDC25 phosphatases and checkpoint controls
    Draetta, G
    Donzelli, M
    Squatrito, M
    Ganoth, D
    Hershko, A
    Pagano, M
    EUROPEAN JOURNAL OF CANCER, 2002, 38 : S116 - S116
  • [6] Independent mechanistic inhibition of Cdc25 phosphatases by a natural product caulibugulone
    Brisson, Marni
    Foster, Caleb
    Wipf, Peter
    Joo, Beomjun
    Tomko, Robert J., Jr.
    Nguyen, Theresa
    Lazo, John S.
    MOLECULAR PHARMACOLOGY, 2007, 71 (01) : 184 - 192
  • [7] CDC25A: A Rebel Within the CDC25 Phosphatases Family?
    Fernandez-Vidal, Anne
    Mazars, Anne
    Manenti, Stephane
    ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, 2008, 8 (08) : 825 - 831
  • [8] Cdc25 phosphatases: Structure, specificity, and mechanism
    Rudolph, Johannes
    BIOCHEMISTRY, 2007, 46 (12) : 3595 - 3604
  • [9] Cdc25 protein phosphatases in cell proliferation
    Draetta, G.
    Eckstein, J.
    B B A - Biomembranes, 1332 (02):
  • [10] CDC25 PHOSPHATASES AS POTENTIAL HUMAN ONCOGENES
    GALAKTIONOV, K
    LEE, AK
    ECKSTEIN, J
    DRAETTA, G
    MECKLER, J
    LODA, M
    BEACH, D
    SCIENCE, 1995, 269 (5230) : 1575 - 1577