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Nature. 2017 Oct 26;550(7677):481-486. doi: 10.1038/nature24451. Epub 2017 Oct 18.

Molecular basis of USP7 inhibition by selective small-molecule inhibitors.

Author information

1
CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre, London NW1 0NH, UK.
2
FORMA Therapeutics, Arsenal Street, Watertown, Massachusetts 02472, USA.
3
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7FZ, UK.
4
Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
5
CRUK Therapeutic Discovery Laboratories, Jonas Webb Building, Babraham Research Campus, Cambridge CB22 3AT, UK.
6
Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.

Abstract

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.

PMID:
29045389
PMCID:
PMC6029662
DOI:
10.1038/nature24451
[Indexed for MEDLINE]
Free PMC Article

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