Structure-Guided Development of a Potent and Selective Non-covalent Active-Site Inhibitor of USP7

Cell Chem Biol. 2017 Dec 21;24(12):1490-1500.e11. doi: 10.1016/j.chembiol.2017.09.003. Epub 2017 Oct 19.


Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5-10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies. Due to a lack of high-resolution DUB⋅small-molecule ligand complex structures, no structure-guided optimization efforts have been reported for a mammalian DUB. Here, we report a small-molecule⋅ubiquitin-specific protease (USP) family DUB co-structure and rapid design of potent and selective inhibitors of USP7 guided by the structure. Interestingly, the compounds are non-covalent active-site inhibitors.

Keywords: DUB; HAUSP; USP7; chemical probe; complex structure; crystal structure; crystallography; deubiquitinating enzyme.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Ubiquitin / metabolism
  • Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors*
  • Ubiquitin-Specific Peptidase 7 / metabolism


  • 1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone
  • P5091
  • Protease Inhibitors
  • Thiophenes
  • Ubiquitin
  • Ubiquitin-Specific Peptidase 7