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

共 50 条

[31] Elastic network models and molecular dynamic simulations reveal the molecular basis of allosteric regulation in ubiquitin-specific protease 7 (USP7)
Xu, Jing
Wang, Yiran
Zhang, Jiali
Abdelmoneim, Amr Abbas
Liang, Zhongjie
Wang, Lei
Jin, Jia
Dai, Qi
Ye, Fei
COMPUTERS IN BIOLOGY AND MEDICINE, 2023, 162
[32] Small-Molecule Inhibitors of USP1 Target ID1 Degradation in Leukemic Cells
Mistry, Helena
Hsieh, Grace
Buhrlage, Sara J.
Huang, Min
Park, Eunmi
Cuny, Gregory D.
Galinsky, Ilene
Stone, Richard M.
Gray, Nathanael S.
D'Andrea, Alan D.
Parmar, Kalindi
MOLECULAR CANCER THERAPEUTICS, 2013, 12 (12) : 2651 - 2662
[33] Small-molecule MDM2 inhibitors in clinical trials for cancer therapy
Wang, Shuai
Chen, Fen-Er
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2022, 236
[34] Small-molecule MDM2-p53 inhibitors: recent advances
Zhang, Bian
Golding, Bernard T.
Hardcastle, Ian R.
FUTURE MEDICINAL CHEMISTRY, 2015, 7 (05) : 631 - 645
[35] Selective inhibition of intestinal guanosine 3,5-cyclic monophosphate signaling by small-molecule protein kinase inhibitors
Bijvelds, Marcel J. C.
Tresadern, Gary
Hellemans, Ann
Smans, Karine
Nieuwenhuijze, Natascha D. A.
Meijsen, Kelly F.
Bongartz, Jean-Pierre
Ver Donck, Luc
de Jonge, Hugo R.
Schuurkes, Jan A. J.
De Maeyer, Joris H.
JOURNAL OF BIOLOGICAL CHEMISTRY, 2018, 293 (21) : 8173 - 8181
[36] Identification and Structure-Guided Development of Pyrimidinone Based USP7 Inhibitors
O'Dowd, Colin R.
Helm, Matthew D.
Rountree, J. S. Shane
Flasz, Jakub T.
Arkoudis, Elias
Miel, Hugues
Hewitt, Peter R.
Jordan, Linda
Barker, Oliver
Hughes, Caroline
Rozycka, Ewelina
Cassidy, Eamon
McClelland, Keeva
Odrzywol, Ewa
Page, Natalie
Feutren-Burton, Stephanie
Dvorkin, Scarlett
Gavory, Gerald
Harrison, Timothy
ACS MEDICINAL CHEMISTRY LETTERS, 2018, 9 (03): : 238 - 243
[37] The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule
Cross, Benedict C. S.
Bond, Peter J.
Sadowski, Pawel G.
Jha, Babal Kant
Zak, Jaroslav
Goodman, Jonathan M.
Silverman, Robert H.
Neubert, Thomas A.
Baxendale, Ian R.
Ron, David
Harding, Heather P.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (15) : E869 - E878
[38] Halogen Substituents in the Isoquinoline Scaffold Switches the Selectivity of Inhibition between USP2 and USP7
Vamisetti, Ganga B.
Meledin, Roman
Gopinath, Pushparathinam
Brik, Ashraf
CHEMBIOCHEM, 2019, 20 (02) : 282 - 286
[39] Plk1-Targeted Small Molecule Inhibitors: Molecular Basis for Their Potency and Specificity
Murugan, Ravichandran N.
Park, Jung-Eun
Kim, Eun-Hee
Shin, Song Yub
Cheong, Chaejoon
Lee, Kyung S.
Bang, Jeong Kyu
MOLECULES AND CELLS, 2011, 32 (03) : 209 - 220
[40] Structural basis of small-molecule inhibition of human multidrug transporter ABCG2
Jackson, Scott M.
Manolaridis, Ioannis
Kowal, Julia
Zechner, Melanie
Taylor, Nicholas M. I.
Bause, Manuel
Bauer, Stefanie
Bartholomaeus, Ruben
Bernhardt, Guenther
Koenig, Burkhard
Buschauer, Armin
Stahlberg, Henning
Altmann, Karl-Heinz
Locher, Kaspar P.
NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2018, 25 (04) : 333 - +

← 1 2 3 4 5 →