Targeting USP7 to reactivate the body's natural defenses against tumors
Within every cell in our body, a microscopic tug-of-war constantly plays out, determining whether proteins crucial for preventing cancer are preserved or destroyed. At the center of this battle stands USP7 (Ubiquitin-Specific Protease 7), a enzyme that acts as a master regulator of protein stability. When functioning properly, USP7 helps maintain cellular equilibrium. But when hijacked by cancer, it becomes a powerful ally to the disease, protecting the very proteins that drive uncontrolled growth 1 .
Ubiquitin-specific protease 7 belongs to a family of enzymes called deubiquitinases (DUBs), which function as molecular editors that remove ubiquitin tags from proteins 1 2 .
The architecture of USP7 is uniquely suited to its complex role. It features multiple domains, including a catalytic domain where the actual deubiquitination occurs 1 .
While initially studied for its relationship with the famous tumor suppressor p53, USP7's influence extends far beyond this single pathway. The enzyme regulates a diverse network of proteins involved in cell division, DNA repair, and immune response 1 2 .
The development of USP7 inhibitors illustrates the progression of modern drug discovery—from initial unselective compounds to highly specific therapeutic candidates.
Representative Compounds: HBX 41108, P22077, P5091 4 6
Mechanism: Irreversible covalent binding to catalytic cysteine
Representative Compounds: FT671, USP7-797 3 6
Mechanism: Non-covalent active site inhibition
A recent groundbreaking study published in 2025 detailed the characterization of OAT-4828, a novel USP7 inhibitor with a profile suitable for oral administration 3 .
The findings revealed several remarkable aspects of OAT-4828's activity with potent inhibition in the nanomolar range 3 .
| Cancer Model | USP7 Inhibition (IC50) | Tumor Growth Inhibition |
|---|---|---|
| Melanoma (B16F10) | Low nanomolar range | Significant reduction |
| Colon Cancer (CT26) | Low nanomolar range | Significant reduction |
| T-cell depleted models | Same potency | Greatly reduced effect |
OAT-4828 works through direct cancer cell death induction while simultaneously unleashing an immune attack against the tumor 3 .
V517F mutation in USP7 gene reduces drug effectiveness, but next-generation inhibitors can overcome this resistance 6 .
Potent activity against acute myeloid leukemia cells, with strong synergistic effects when combined with venetoclax .
Preclinical
Current StagePhase I
SafetyPhase II
EfficacyPhase III
ConfirmationApproval
RegulatoryClinical Use
PatientsThe journey to target USP7 therapeutically represents a microcosm of modern cancer drug development—from basic biological understanding to targeted intervention. Once an obscure component of cellular machinery, USP7 has been transformed into one of the most promising targets in oncology.
What makes USP7 particularly compelling as a target is its dual mechanism of action—simultaneously attacking cancer cells directly while enlisting the immune system as an ally. While no USP7 inhibitor has yet entered clinical trials, the accelerating pace of discovery suggests that this milestone may not be far off.