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Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes

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Published copy (DOI)

Author(s)

  • Mikael Altun
  • Holger B. Kramer
  • Lianne I. Willems
  • Jeffrey L. McDermott
  • Craig A. Leach
  • Seth J. Goldenberg
  • K. G Suresh Kumar
  • Rebecca Konietzny
  • Roman Fischer
  • Edward Kogan
  • Mukram M. MacKeen
  • Joanna McGouran
  • Svetlana V. Khoronenkova
  • Jason L. Parsons
  • Grigory L. Dianov
  • Benjamin Nicholson
  • Benedikt M Kessler

Department/unit(s)

Publication details

JournalChemistry & Biology
DatePublished - 23 Nov 2011
Issue number11
Volume18
Number of pages12
Pages (from-to)1401-1412
Original languageEnglish

Abstract

Converting lead compounds into drug candidates is a crucial step in drug development, requiring early assessment of potency, selectivity, and off-target effects. We have utilized activity-based chemical proteomics to determine the potency and selectivity of deubiquitylating enzyme (DUB) inhibitors in cell culture models. Importantly, we characterized the small molecule PR-619 as a broad-range DUB inhibitor, and P22077 as a USP7 inhibitor with potential for further development as a chemotherapeutic agent in cancer therapy. A striking accumulation of polyubiquitylated proteins was observed after both selective and general inhibition of cellular DUB activity without direct impairment of proteasomal proteolysis. The repertoire of ubiquitylated substrates was analyzed by tandem mass spectrometry, identifying distinct subsets for general or specific inhibition of DUBs. This enabled identification of previously unknown functional links between USP7 and enzymes involved in DNA repair.

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