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Structure-Guided Discovery of OAT-4828 as Potent, Selective, and Orally Bioavailable USP7 Inhibitor with In Vivo

Jacek Chrzanowski1, Julita Nowicka1, Robert Koralewski1

  • 1Molecure S.A., Żwirki i Wigury 101, 02-089 Warsaw, Poland.

Journal of Medicinal Chemistry
|May 6, 2026
PubMed

Insights

Researchers developed a potent and selective USP7 inhibitor, OAT-4828, by optimizing existing scaffolds. This compound demonstrated significant antileukemic activity in preclinical models, highlighting its therapeutic potential for B-cell non-Hodgkin lymphoma.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme crucial in cancer progression through protein stabilization.
  • Targeting USP7 offers a therapeutic strategy for various cancers.

Purpose of the Study:

  • To design and synthesize selective USP7 inhibitors using a structure-based approach.
  • To identify a potent and safe tool compound for in vivo studies.

Main Methods:

  • Structure-based drug design and scaffold modification.
  • In vitro biochemical assays for inhibitory potency and selectivity.
  • Pharmacokinetic and preliminary safety assessments in mice.
  • In vivo efficacy testing in a syngeneic lymphoma model.

Main Results:

  • Optimization of allosteric USP7 ligand scaffolds yielded potent inhibitors.
  • Structural modifications improved selectivity and reduced off-target liabilities.
  • Lead compound OAT-4828 exhibited favorable pharmacokinetics and safety in mice.
  • OAT-4828 demonstrated significant antileukemic activity in a B-cell lymphoma model.

Conclusions:

  • OAT-4828 is a potent, selective USP7 inhibitor with promising therapeutic potential.
  • The developed compound serves as a valuable tool for further in vivo research.
  • USP7 inhibition represents a viable strategy for treating B-cell non-Hodgkin lymphoma.

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