USP7 small-molecule inhibitors interfere with ubiquitin binding

Journal: Nature

Published: 2017-10-18

DOI: 10.1038/nature24006

Affiliations: 15

Authors: 44

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Research Highlight

A circuitous approach to cancer therapy



Many proteins implicated in cancer growth and survival are extremely difficult to target directly with drugs, but scientists at Genentech, a Roche subsidiary, have found a roundabout therapeutic strategy for limiting the activity of these otherwise intractable proteins.

Reporting in Nature, a Genentech-led team has identified two small molecule inhibitors of ubiquitin-specific protease-7 (USP7), an enzyme that strips other proteins of small tags that mark them for destruction by the cell’s garbage disposal system.

These drugs, by blocking USP7 near its active site, set off a molecular chain reaction that helps stabilize a master tumour suppressor protein called p53, an elusive “undruggable” target. In lab experiments, the molecules killed cancer cells in a dish and augmented the anti-tumour effects of other chemotherapeutic agents.

The compounds lack certain properties required for human use, and so further drug development efforts are still needed to build on the finding of this anti-USP7 strategy.

Supported content

  1. Nature 550, 534–538 (2017). doi: 10.1038/nature24006
Institutions Share
Genentech, Inc., United States of America (USA) 0.75
University of California, San Francisco (UCSF), United States of America (USA) 0.11
Boston Biochem Inc., United States of America (USA) 0.07
MRC Protein Phosphorylation and Ubiquitylation Unit (PPU), University of Dundee, United Kingdom (UK) 0.05
Newcastle University, United Kingdom (UK) 0.02