Molecular basis of USP7 inhibition by selective small-molecule inhibitors

被引：332

作者：

Turnbull, Andrew P. ^{[1
]}

Ioannidis, Stephanos ^{[2
]}

Krajewski, Wojciech W. ^{[1
]}

Pinto-Fernandez, Adan ^{[3
]}

Heride, Claire ^{[4
]}

Martin, Agnes C. L. ^{[5
]}

Tonkin, Louise M. ^{[5
]}

Townsend, Elizabeth C. ^{[2
]}

Buker, Shane M. ^{[2
,7
]}

Lancia, David R., Jr. ^{[2
]}

Caravella, Justin A. ^{[2
]}

Toms, Angela V. ^{[2
]}

Charlton, Thomas M. ^{[3
,8
]}

Lahdenranta, Johanna ^{[2
]}

Wilker, Erik ^{[2
]}

Follows, Bruce C. ^{[2
]}

Evans, Nicola J. ^{[1
,9
]}

Stead, Lucy ^{[4
]}

Alli, Cristina ^{[5
]}

Zarayskiy, Vladislav V. ^{[2
]}

Talbot, Adam C. ^{[2
]}

Buckmelter, Alexandre J. ^{[2
]}

Wang, Minghua ^{[2
]}

McKinnon, Crystal L. ^{[2
]}

Saab, Fabienne ^{[1
]}

McGouran, Joanna F. ^{[3
,10
]}

Century, Hannah ^{[3
,11
]}

Gersch, Malte ^{[6
]}

Pittman, Marc S. ^{[1
,12
]}

Marshall, C. Gary ^{[2
]}

Raynham, Tony M. ^{[1
,13
]}

Simcox, Mary ^{[2
,14
]}

Stewart, Lorna M. D. ^{[1
]}

McLoughlin, Sheila B. ^{[5
]}

Escobedo, Jaime A. ^{[2
]}

Bair, Kenneth W. ^{[2
,15
]}

Dinsmore, Christopher J. ^{[2
]}

Hammonds, Tim R. ^{[1
]}

Kim, Sunkyu ^{[2
]}

Urbe, Sylvie ^{[4
]}

Clague, Michael J. ^{[4
]}

Kessler, Benedikt M. ^{[3
]}

Komander, David ^{[6
]}

机构：

[1] London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England

[2] FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA

[3] Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Roosevelt Dr, Oxford OX3 7FZ, England

[4] Univ Liverpool, Inst Translat Med, Cellular & Mol Physiol, Crown St, Liverpool L69 3BX, Merseyside, England

[5] CRUK Therapeut Discovery Labs, Jonas Webb Bldg,Babraham Res Campus, Cambridge CB22 3AT, England

[6] MRC, Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England

[7] Goldfinch Bio, Cambridge, MA 02142 USA

[8] Univ Chicago, Dept Microbiol, CLSC 1117, Chicago, IL 60637 USA

[9] Kings Coll London, Dept Chem, London SE1 1DB, England

[10] Trinity Coll Dublin, Coll Green, Dublin 2, Ireland

[11] UCL, London WC1E 6BT, England

[12] CRUK Ctr Drug Dev, London EC1V 4AD, England

[13] Univ East London, Sch Hlth Sport & Biosci, Stratford Campus, London E15 4LZ, England

[14] Tarveda Therapeut, Watertown, MA 02472 USA

[15] Athelas Therapeut, Wellesley, MA 02432 USA

来源：

NATURE | 2017年 / 550卷 / 7677期

基金：

英国惠康基金; 英国工程与自然科学研究理事会; 英国医学研究理事会; 欧洲研究理事会;

关键词：

DEUBIQUITINATING ENZYME; UBIQUITIN SYSTEM; CATALYTIC DOMAIN; CANCER-THERAPY; GMP-SYNTHETASE; P53; PATHWAY; CELLS; ACTIVATION; PROTEASES;

D O I：

10.1038/nature24451

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice.

引用

页码：481 / +

页数：21

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