Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes

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, Muhammad Mukram Mohamed Mackeen, Joanna McGouran, Svetlana V. Khoronenkova, Jason L. Parsons, Grigory L. Dianov, Benjamin Nicholson, Benedikt M. Kessler

Research output: Contribution to journalArticle

176 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1401-1412
Number of pages12
JournalChemistry and Biology
Volume18
Issue number11
DOIs
Publication statusPublished - 23 Nov 2011
Externally publishedYes

Fingerprint

Enzyme Inhibitors
Proteomics
Proteolysis
Lead compounds
Enzyme inhibition
Enzyme activity
Enzymes
Tandem Mass Spectrometry
Cell culture
DNA Repair
Pharmaceutical Preparations
Mass spectrometry
Repair
Cell Culture Techniques
Molecules
DNA
Substrates
Neoplasms
Proteins
Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Altun, M., Kramer, H. B., Willems, L. I., McDermott, J. L., Leach, C. A., Goldenberg, S. J., ... Kessler, B. M. (2011). Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chemistry and Biology, 18(11), 1401-1412. https://doi.org/10.1016/j.chembiol.2011.08.018

Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. / Altun, Mikael; Kramer, Holger B.; Willems, Lianne I.; McDermott, Jeffrey L.; Leach, Craig A.; Goldenberg, Seth J.; Kumar, K. G Suresh; Konietzny, Rebecca; Fischer, Roman; Kogan, Edward; Mohamed Mackeen, Muhammad Mukram; McGouran, Joanna; Khoronenkova, Svetlana V.; Parsons, Jason L.; Dianov, Grigory L.; Nicholson, Benjamin; Kessler, Benedikt M.

In: Chemistry and Biology, Vol. 18, No. 11, 23.11.2011, p. 1401-1412.

Research output: Contribution to journalArticle

Altun, M, Kramer, HB, Willems, LI, McDermott, JL, Leach, CA, Goldenberg, SJ, Kumar, KGS, Konietzny, R, Fischer, R, Kogan, E, Mohamed Mackeen, MM, McGouran, J, Khoronenkova, SV, Parsons, JL, Dianov, GL, Nicholson, B & Kessler, BM 2011, 'Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes', Chemistry and Biology, vol. 18, no. 11, pp. 1401-1412. https://doi.org/10.1016/j.chembiol.2011.08.018
Altun M, Kramer HB, Willems LI, McDermott JL, Leach CA, Goldenberg SJ et al. Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chemistry and Biology. 2011 Nov 23;18(11):1401-1412. https://doi.org/10.1016/j.chembiol.2011.08.018
Altun, Mikael ; Kramer, Holger B. ; Willems, Lianne I. ; McDermott, Jeffrey L. ; Leach, Craig A. ; Goldenberg, Seth J. ; Kumar, K. G Suresh ; Konietzny, Rebecca ; Fischer, Roman ; Kogan, Edward ; Mohamed Mackeen, Muhammad Mukram ; McGouran, Joanna ; Khoronenkova, Svetlana V. ; Parsons, Jason L. ; Dianov, Grigory L. ; Nicholson, Benjamin ; Kessler, Benedikt M. / Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. In: Chemistry and Biology. 2011 ; Vol. 18, No. 11. pp. 1401-1412.
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