Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Sci Rep. 2020 Mar 24;10(1):5324. doi: 10.1038/s41598-020-62076-x.


Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multi-substrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structure-guided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of ~500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • MCF-7 Cells
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors*
  • Ubiquitin-Specific Peptidase 7 / chemistry
  • Ubiquitin-Specific Peptidase 7 / metabolism
  • Ubiquitination / drug effects


  • Antineoplastic Agents
  • Protease Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7