Journal of medicinal chemistry · 2026
Structure-Guided Discovery of OAT-4828 as Potent, Selective, and Orally Bioavailable USP7 Inhibitor with In Vivo Antileukemic Activity.
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Chrzanowski Jacek, Nowicka Julita, Koralewski Robert, Joachimiak Lukasz, Gzik Anna, Borek Bartlomiej, Brzezinska Joanna, Kusmirek Damian, Olejniczak Sylwia, Matyszewski Krzysztof, Mazur Marzena, Olczak Jacek, Glatt Sebastian, Grudnik Przemysław, Wilk Piotr, Muchowicz Angelika, Kikulska Agnieszka, Gluchowska Katarzyna M, Drzewicka Katarzyna, Belczyk-Ciesielska Agnieszka, Wachowska Malgorzata, Sipak-Bujanowicz Zuzanna, Mulewski Krzysztof, Tkaczyk Agnieszka, Rejczak Tomasz, Golebiowski Adam, Zaslona Zbigniew, Blaszczyk Roman
Аннотация
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.