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

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.