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; Mukram M Mackeen; Joanna McGouran; Svetlana V Khoronenkova; Jason L Parsons; Grigory L Dianov; Benjamin Nicholson; Benedikt M Kessler

doi:10.1016/j.chembiol.2011.08.018

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

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	1401-12
Number of pages	12
Journal	Chemistry & Biology
Volume	18
Issue number	11
DOIs	https://doi.org/10.1016/j.chembiol.2011.08.018
Publication status	Published - 23 Nov 2011

Bibliographical note

Keywords

Aminopyridines/chemistry
Antibodies/chemistry
Cell Line
Chromatography, High Pressure Liquid
Enzyme Activation/drug effects
Enzyme Inhibitors/chemistry
Humans
Proteomics
RNA Interference
Tandem Mass Spectrometry
Thiocyanates/chemistry
Thiophenes/chemistry
Ubiquitin Thiolesterase/antagonists & inhibitors
Ubiquitin-Specific Peptidase 7

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2011.08.018

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Altun, M., Kramer, H. B., Willems, L. I., McDermott, J. L., Leach, C. A., Goldenberg, S. J., Kumar, K. G. S., Konietzny, R., Fischer, R., Kogan, E., Mackeen, M. M., McGouran, J., Khoronenkova, S. V., Parsons, J. L., Dianov, G. L., Nicholson, B., & Kessler, B. M. (2011). Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes. Chemistry & Biology, 18(11), 1401-12. https://doi.org/10.1016/j.chembiol.2011.08.018

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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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doi = "10.1016/j.chembiol.2011.08.018",

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Altun, M, Kramer, HB, Willems, LI, McDermott, JL, Leach, CA, Goldenberg, SJ, Kumar, KGS, Konietzny, R, Fischer, R, Kogan, E, 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 & Biology, vol. 18, no. 11, pp. 1401-12. https://doi.org/10.1016/j.chembiol.2011.08.018

TY - JOUR

T1 - Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes

AU - Altun, Mikael

AU - Kramer, Holger B

AU - Willems, Lianne I

AU - McDermott, Jeffrey L

AU - Leach, Craig A

AU - Goldenberg, Seth J

AU - Kumar, K G Suresh

AU - Konietzny, Rebecca

AU - Fischer, Roman

AU - Kogan, Edward

AU - Mackeen, Mukram M

AU - McGouran, Joanna

AU - Khoronenkova, Svetlana V

AU - Parsons, Jason L

AU - Dianov, Grigory L

AU - Nicholson, Benjamin

AU - Kessler, Benedikt M

PY - 2011/11/23

Y1 - 2011/11/23

N2 - 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.

AB - 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.

KW - Aminopyridines/chemistry

KW - Antibodies/chemistry

KW - Cell Line

KW - Chromatography, High Pressure Liquid

KW - Enzyme Activation/drug effects

KW - Enzyme Inhibitors/chemistry

KW - Humans

KW - Proteomics

KW - RNA Interference

KW - Tandem Mass Spectrometry

KW - Thiocyanates/chemistry

KW - Thiophenes/chemistry

KW - Ubiquitin Thiolesterase/antagonists & inhibitors

KW - Ubiquitin-Specific Peptidase 7

U2 - 10.1016/j.chembiol.2011.08.018

DO - 10.1016/j.chembiol.2011.08.018

M3 - Article

C2 - 22118674

SN - 1074-5521

VL - 18

SP - 1401

EP - 1412

JO - Chemistry & Biology

JF - Chemistry & Biology

IS - 11

ER -

Activity-based chemical proteomics accelerates inhibitor development for deubiquitylating enzymes

Abstract

Bibliographical note

Keywords

UN SDGs

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