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

© KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty

© KATERYNA KON/SCIENCE PHOTO LIBRARY/Getty

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 FC
Department of Discovery Oncology, Genentech, Inc., United States of America (USA) 0.11
Department of Discovery Chemistry, Genentech, Inc., United States of America (USA) 0.11
Department of Biochemical and Cellular Pharmacology, Genentech, Inc., United States of America (USA) 0.11
Department of Structural Biology, Genentech, Inc., United States of America (USA) 0.09
Department of Bioinformatics and Computational Biology, Genentech, Inc., United States of America (USA) 0.09
Department of Early Discovery Biochemistry, Genentech, Inc., United States of America (USA) 0.07
Department of Protein Chemistry and Structural Biology, Genentech, Inc., United States of America (USA) 0.07
Boston Biochem Inc., United States of America (USA) 0.07
UCSF Department of Pharmaceutical Chemistry, United States of America (USA) 0.06
UCSF Small Molecule Discovery Center (SMDC), United States of America (USA) 0.06
MRC Protein Phosphorylation and Ubiquitylation Unit (PPU), University of Dundee, United Kingdom (UK) 0.05
Department of Microchemistry, Proteomics and Lipidomics (MPL), Genentech, Inc., United States of America (USA) 0.05
Institute for Cell and Molecular Biosciences (ICaMB), Newcastle University, United Kingdom (UK) 0.02
Genentech, Inc., United States of America (USA) 0.02
Department of Translational Oncology, Genentech, Inc., United States of America (USA) 0.02

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