2. Academic Validation
  3. Structure-Guided Discovery of OAT-4828 as Potent, Selective, and Orally Bioavailable USP7 Inhibitor with In Vivo Antileukemic Activity

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

  • J Med Chem. 2026 May 28;69(10):12502-12518. doi: 10.1021/acs.jmedchem.6c00407.
Jacek Chrzanowski 1,  Julita Nowicka 1,  Robert Koralewski 1,  Lukasz Joachimiak 1,  Anna Gzik 1,  Bartlomiej Borek 1,  Joanna Brzezinska 1,  Damian Kusmirek 1,  Sylwia Olejniczak 1,  Krzysztof Matyszewski 1,  Marzena Mazur 1,  Jacek Olczak 1,  Sebastian Glatt 2,  Przemysław Grudnik 2,  Piotr Wilk 2,  Angelika Muchowicz 1 3,  Agnieszka Kikulska 1,  Katarzyna M Gluchowska 1,  Katarzyna Drzewicka 1,  Agnieszka Belczyk-Ciesielska 1,  Malgorzata Wachowska 4,  Zuzanna Sipak-Bujanowicz 1,  Krzysztof Mulewski 1,  Agnieszka Tkaczyk 1,  Tomasz Rejczak 1,  Adam Golebiowski 1,  Zbigniew Zaslona 1,  Roman Blaszczyk 1
Affiliations

Affiliations

  • 1 Molecure S.A., Żwirki i Wigury 101, 02-089 Warsaw, Poland.
  • 2 Jagiellonian University, Malopolska Centre of Biotechnology, Gronostajowa 7A, 30-387 Krakow, Poland.
  • 3 Laboratory of Cellular and Genetic Therapies, Center for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland.
  • 4 Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Zwirki i Wigury 63A, 02-091 Warsaw, Poland.
PMID: 42090583 DOI: 10.1021/acs.jmedchem.6c00407
Abstract

Ubiquitin-Specific Protease 7 (USP7) is a deubiquitinating enzyme implicated in Cancer development via stabilization of oncogenic proteins and immunosuppressive factors. We used a structure-based approach to design selective USP7 inhibitors to exploit this therapeutic target. Starting from allosteric USP7 ligand scaffolds, we introduced several structural modifications that generally preserved high inhibitory potency. Additionally, rigidification of a benzylic linkage mitigated off-target liability identified for the reference compound. This optimization led to the potent, USP7-selective lead compound 45 (OAT-4828). Its pharmacokinetic profile in mice and preliminary safety assessments of the molecule encouraged us to use OAT-4828 as a tool compound for in vivo investigations. OAT-4828 was well-tolerated in mice, demonstrating significant antileukemic activity in a syngeneic model of B-cell derived non-Hodgkin lymphoma.

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