Activity-Based Chemical Proteomics Accelerates Inhibitor Development for Deubiquitylating Enzymes

被引：365

作者：

Altun, Mikael ^{[1
]}

Kramer, Holger B. ^{[1
]}

Willems, Lianne I. ^{[1
]}

McDermott, Jeffrey L. ^{[3
]}

Leach, Craig A. ^{[3
]}

Goldenberg, Seth J. ^{[3
]}

Kumar, K. G. Suresh ^{[3
]}

Konietzny, Rebecca ^{[1
]}

Fischer, Roman ^{[1
]}

Kogan, Edward ^{[1
]}

Mackeen, Mukram M. ^{[1
]}

McGouran, Joanna ^{[1
]}

Khoronenkova, Svetlana V. ^{[2
]}

Parsons, Jason L. ^{[2
]}

Dianov, Grigory L. ^{[2
]}

Nicholson, Benjamin ^{[3
]}

Kessler, Benedikt M. ^{[1
]}

机构：

[1] Univ Oxford, Nuffield Dept Med, Oxford OX3 7DQ, England

[2] Univ Oxford, Gray Inst Radiat Oncol & Biol, Dept Oncol, Oxford OX3 7DQ, England

[3] Progenra Inc, Malvern, PA 19355 USA

来源：

CHEMISTRY & BIOLOGY | 2011年 / 18卷 / 11期

基金：

瑞典研究理事会;

关键词：

FUNCTIONAL PROTEOMICS; UBIQUITIN; HAUSP; P53; DEUBIQUITINATION; CHEMISTRY; CANCER; IDENTIFICATION; ACTIVATION; STABILIZES;

D O I：

10.1016/j.chembiol.2011.08.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：1401 / 1412

页数：12

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