Discovery of a Potent and Selective Degrader for USP7

Angew Chem Int Ed Engl. 2022 Aug 15;61(33):e202204395. doi: 10.1002/anie.202204395. Epub 2022 Jul 7.

Abstract

The tumor suppressor p53 is the most frequently mutated gene in human cancer and more than half of cancers contain p53 mutations. The development of novel and effective therapeutic strategies for p53 mutant cancer therapy is a big challenge and highly desirable. Ubiquitin-specific protease 7 (USP7), also known as HAUSP, is a deubiquitinating enzyme and proposed to stabilize the oncogenic E3 ubiquitin ligase MDM2 that promotes the proteosomal degradation of p53. Herein, we report the design and characterization of U7D-1 as the first selective USP7-degrading Proteolysis Targeting Chimera (PROTAC). U7D-1 showed selective and effective USP7 degradation, and maintained potent cell growth inhibition in p53 mutant cancer cells, with USP7 inhibitor showing no activity. These data clearly demonstrated the practicality and importance of PROTAC as a preliminary chemical tool for investigating USP7 protein functions and a promising method for potential p53 mutant cancer therapy.

Keywords: Apoptotic Pathway; Mutant p53; PROTAC; USP7 Degrader; p53 Mutant Cancer Cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Neoplasms* / metabolism
  • Proteolysis
  • Tumor Suppressor Protein p53* / genetics
  • Tumor Suppressor Protein p53* / metabolism
  • Ubiquitin Thiolesterase / chemistry
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Specific Peptidase 7 / metabolism

Substances

  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7