Inhibition of Cdc25 phosphatases by indolyldihydroxyquinones

Jungsan Sohn, Brendan Kiburz, Zhitao Li, Liu Deng, Alexias Safi, Michael C. Pirrung, Johannes Rudolph

Research output: Contribution to journalArticle

Abstract

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 indolyldihydroxyquinones, 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 Kis 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.

Original languageEnglish (US)
Pages (from-to)2580-2588
Number of pages9
JournalJournal of medicinal chemistry
Volume46
Issue number13
DOIs
StatePublished - Jun 19 2003
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Sohn, J., Kiburz, B., Li, Z., Deng, L., Safi, A., Pirrung, M. C., & Rudolph, J. (2003). Inhibition of Cdc25 phosphatases by indolyldihydroxyquinones. Journal of medicinal chemistry, 46(13), 2580-2588. https://doi.org/10.1021/jm0300835