Jacek Chrzanowski, Julita Nowicka, Robert Koralewski, Łukasz Joachimiak, Anna Gzik, Bartłomiej Borek, Joanna Brzezinska, Damian Kusmirek, Sylwia Olejniczak, Krzysztof Matyszewski, Marzena Mazur, Jacek Olczak, Sebastian Glatt, P. Grudnik, P. Wilk, Angelika Muchowicz, Agnieszka Kikulska, Katarzyna M. Głuchowska, Katarzyna Drzewicka, Agnieszka Belczyk-Ciesielska, Małgorzata Wachowska, Zuzanna Sipak-Bujanowicz, Krzysztof Mulewski, Agnieszka Tkaczyk, Tomasz Rejczak, Adam Gołȩbiowski, Zbigniew Zasłona, Roman Błaszczyk
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.