Chemical Approaches to Intervening in Ubiquitin Specific Protease 7 (USP7) Function for Oncology and Immune Oncology Therapies

J Med Chem. 2018 Jan 25;61(2):422-443. doi: 10.1021/acs.jmedchem.7b00498. Epub 2017 Aug 18.

Abstract

Ubiquitin specific protease 7 (USP7), the most widely studied among the nearly 100 deubiquitinating enzymes, supports cancer by positively affecting tumor growth and negatively affecting the patient's immune response to tumors. Great interest exists, therefore, in developing USP7 inhibitors for clinical evaluation. While the proteasome inhibitor field has enjoyed clinical success, very few clinically appropriate effectors of deubiquitinating (protease) or ubiquitinating (ligase) enzymes have appeared. The ubiquitin protease/ligase field is moving from the initial discovery of potent, selective modulators with cell proof of concept and in vivo activity to the optimization of these molecules to impart drug-like properties or the discovery of new inhibitor scaffolds by improved screening or rational design. This Perspective focuses on the current status of USP7 inhibitors from various organizations active in developing these compounds for the clinic and suggests undertakings that are both achievable and necessary to lead to successful clinical outcomes for USP7 inhibitors in cancer treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Clinical Trials as Topic
  • Crystallography, X-Ray
  • Drug Evaluation, Preclinical / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Targeted Therapy / methods
  • Proteasome Inhibitors / pharmacology
  • Protein Conformation
  • Ubiquitin / metabolism
  • Ubiquitin-Specific Peptidase 7 / antagonists & inhibitors*
  • Ubiquitin-Specific Peptidase 7 / chemistry
  • Ubiquitin-Specific Peptidase 7 / immunology
  • Ubiquitin-Specific Peptidase 7 / metabolism*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Proteasome Inhibitors
  • Ubiquitin
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7