Discovery of specific inhibitors of human USP7/HAUSP deubiquitinating enzyme

Chem Biol. 2012 Apr 20;19(4):467-77. doi: 10.1016/j.chembiol.2012.02.007.


The human USP7 deubiquitinating enzyme was shown to regulate many proteins involved in the cell cycle, as well as tumor suppressors and oncogenes. Thus, USP7 offers a promising, strategic target for cancer therapy. Using biochemical assays and activity-based protein profiling in living systems, we identified small-molecule antagonists of USP7 and demonstrated USP7 inhibitor occupancy and selectivity in cancer cell lines. These compounds bind USP7 in the active site through a covalent mechanism. In cancer cells, these active-site-targeting inhibitors were shown to regulate the level of several USP7 substrates and thus recapitulated the USP7 knockdown phenotype that leads to G1 arrest in colon cancer cells. The data presented in this report provide proof of principle that USP7 inhibitors may be a valuable therapeutic for cancer. In addition, the discovery of such molecules offers interesting tools for studying deubiquitination.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • HCT116 Cells
  • Humans
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Ubiquitin Thiolesterase / antagonists & inhibitors*
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitin-Specific Peptidase 7


  • Enzyme Inhibitors
  • Small Molecule Libraries
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7