Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Turnbull Andrew P.; Ioannidis Stephanos; Krajewski Wojciech W.; Pinto-Fernandez Adan; Heride Claire; Martin Agnes C. L.; Tonkin Louise M.; Townsend Elizabeth C.; Buker Shane M.; Lancia David R. Jr.; Caravella Justin A.; Toms Angela V.; Charlton Thomas M.; Lahdenranta Johanna; Wilker Erik; Follows Bruce C.; Evans Nicola J.; Stead Lucy; Alli Cristina; Zarayskiy Vladislav V.; Talbot Adam C.; Buckmelter Alexandre J.; Wang Minghua; McKinnon Crystal L.; Saab Fabienne; McGouran Joanna F.; Century Hannah; Gersch Malte; Pittman Marc S.; Marshall C. Gary; Raynham Tony M.; Simcox Mary; Stewart Lorna M. D.; McLoughlin Sheila B.; Escobedo Jaime A.; Bair Kenneth W.; Dinsmore Christopher J.; Hammonds Tim R.; Kim Sunkyu; Urbe Sylvie; Clague Michael J.; Kessler Benedikt M.; Komander David

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Molecular basis of USP7 inhibition by selective small-molecule inhibitors

机译：选择性小分子抑制剂抑制USP7的分子基础

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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.

机译：泛素化控制大多数细胞蛋白的稳定性，其失调会导致包括癌症在内的人类疾病。去泛素酶从蛋白质上去除泛素，它们的抑制作用可以诱导所选蛋白质的降解，可能包括其他“无法忍受的”靶标。例如，对泛素特异性蛋白酶7（USP7）的抑制导致致癌E3连接酶MDM2降解，并导致多种癌症中的肿瘤抑制因子p53再次激活。在这里，我们报道了两种化合物FT671和FT827在体外和人类细胞内以高亲和力和特异性抑制USP7。共晶体结构表明，这两种化合物都靶向USP7自动抑制载脂蛋白形式催化中心附近的动态囊袋，这不同于其他USP去泛素酶。与USP7靶标在细胞中的参与一致，FT671使USP7底物（包括MDM2）不稳定，增加了p53的水平，并导致p53靶基因的转录，肿瘤抑制物p21的诱导和小鼠肿瘤生长的抑制。

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《Nature》 |2017年第7677期|481-486|共6页
作者
Turnbull Andrew P.; Ioannidis Stephanos; Krajewski Wojciech W.; Pinto-Fernandez Adan; Heride Claire; Martin Agnes C. L.; Tonkin Louise M.; Townsend Elizabeth C.; Buker Shane M.; Lancia David R. Jr.; Caravella Justin A.; Toms Angela V.; Charlton Thomas M.; Lahdenranta Johanna; Wilker Erik; Follows Bruce C.; Evans Nicola J.; Stead Lucy; Alli Cristina; Zarayskiy Vladislav V.; Talbot Adam C.; Buckmelter Alexandre J.; Wang Minghua; McKinnon Crystal L.; Saab Fabienne; McGouran Joanna F.; Century Hannah; Gersch Malte; Pittman Marc S.; Marshall C. Gary; Raynham Tony M.; Simcox Mary; Stewart Lorna M. D.; McLoughlin Sheila B.; Escobedo Jaime A.; Bair Kenneth W.; Dinsmore Christopher J.; Hammonds Tim R.; Kim Sunkyu; Urbe Sylvie; Clague Michael J.; Kessler Benedikt M.; Komander David;
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作者单位

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England;

Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Roosevelt Dr, Oxford OX3 7FZ, England;

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

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

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

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA|Goldfinch Bio, Cambridge, MA 02142 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Roosevelt Dr, Oxford OX3 7FZ, England|Univ Chicago, Dept Microbiol, CLSC 1117, Chicago, IL 60637 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England|Kings Coll London, Dept Chem, London SE1 1DB, England;

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

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

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England;

Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Roosevelt Dr, Oxford OX3 7FZ, England|Trinity Coll Dublin, Coll Green, Dublin 2, Ireland;

Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Roosevelt Dr, Oxford OX3 7FZ, England|UCL, London WC1E 6BT, England;

MRC, Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England|CRUK Ctr Drug Dev, London EC1V 4AD, England;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England|Univ East London, Sch Hlth Sport & Biosci, Stratford Campus, London E15 4LZ, England;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA|Tarveda Therapeut, Watertown, MA 02472 USA;

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England;

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

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA|Athelas Therapeut, Wellesley, MA 02432 USA;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

London Biosci Innovat Ctr, CRUK Therapeut Discovery Labs, London NW1 0NH, England;

FORMA Therapeut, Arsenal St, Watertown, MA 02472 USA;

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

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

Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Roosevelt Dr, Oxford OX3 7FZ, England;

MRC, Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

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Molecular basis of USP7 inhibition by selective small-molecule inhibitors

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