Harnessing the oxidation susceptibility of deubiquitinases for inhibition with small molecules

Ohayon Shimrit, Refua Maya, Hendler Adi, Aharoni Amir, Brik Ashraf

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Deubiquitinases (DUBs) counteract ubiquitination by removing or trimming ubiquitin chains to alter the signal. Their diverse role in biological processes and involvement in diseases have recently attracted great interest with regard to their mechanism and inhibition. It has been shown that some DUBs are regulated by reactive oxygen species (ROS) in which the catalytic Cys residue undergoes reversible oxidation, hence modulating DUBs activity under oxidative stress. Reported herein for the first time, the observation that small molecules, which are capable of generating ROS efficiently, inhibit DUBs by selective and nonreversible oxidation of the catalytic Cys residue. Interestingly, the small molecule beta-lapachone, which is currently in clinical trials for cancer, is among the potent inhibitors, thus suggesting possible new cellular targets for its therapeutic effects. Our study describes a novel mechanism of DUBs inhibition and opens new opportunities in exploiting them for cancer therapy.

Original languageEnglish
Pages (from-to)599-603
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number2
DOIs
StatePublished - 7 Jan 2015

Keywords

  • Cancer
  • Enzymes
  • Inhibitors
  • Quinones
  • Reactive oxygen species

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