Discovery of USP7 small-molecule allosteric inhibitors

Bioorg Med Chem Lett. 2020 Oct 15;30(20):127471. doi: 10.1016/j.bmcl.2020.127471. Epub 2020 Aug 8.


Ubiquitin specific protease-7 (USP7) is considered an attractive target for cancer therapy by promoting degradation of the tumor suppressor p53 and negatively affecting the immune response to tumors. However, the development of selective non-covalent USP7 inhibitors has proven challenging. In this work we report the NMR characterization of a weak binder from SPR screening of an in-house fragment library which reveals that it binds to the allosteric palm site of the catalytic domain. Molecular modeling combined with 1HNMR saturation transfer difference and NOESY experiments enabled structure-based design of additional compounds showing IC50 values in the low-micromolar range with good selectivity over the closest homolog USP47. The most potent analogue represents a promising starting point for the development of novel, selective USP7 inhibitors.

Keywords: Allosteric; Inhibitors; NMR; USP7; Ubiquitylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site / drug effects
  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors*
  • Ubiquitin-Specific Peptidase 7 / metabolism


  • Amides
  • Small Molecule Libraries
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7