9SZN
Crystal structure of the catalytic domain of USP7 in complex with Compound 43
This is a non-PDB format compatible entry.
Summary for 9SZN
| Entry DOI | 10.2210/pdb9szn/pdb |
| Descriptor | Ubiquitin carboxyl-terminal hydrolase 7, 3-((7-(3-((S)-3-aminopyrrolidine-1-carbonyl)-4-methyl-6-(trifluoromethyl)pyridin-2-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (3 entities in total) |
| Functional Keywords | usp7 inhibitor complex, structure-guided drug design, cancer, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41625.93 |
| Authors | Chrzanowski, J.,Wilk, P.,Grudnik, P.,Nowicka, J.,Koralewski, R.,Joachimiak, L.,Gzik, A.,Borek, B.,Brzezinska, J.,Blaszczyk, R. (deposition date: 2025-10-15, release date: 2026-05-20, Last modification date: 2026-06-03) |
| Primary citation | Chrzanowski, J.,Nowicka, J.,Koralewski, R.,Joachimiak, L.,Gzik, A.,Borek, B.,Brzezinska, J.,Kusmirek, D.,Olejniczak, S.,Matyszewski, K.,Mazur, M.,Olczak, J.,Glatt, S.,Grudnik, P.,Wilk, P.,Muchowicz, A.,Kikulska, A.,Gluchowska, K.M.,Drzewicka, K.,Belczyk-Ciesielska, A.,Wachowska, M.,Sipak-Bujanowicz, Z.,Mulewski, K.,Tkaczyk, A.,Rejczak, T.,Golebiowski, A.,Zaslona, Z.,Blaszczyk, R. Structure-Guided Discovery of OAT-4828 as Potent, Selective, and Orally Bioavailable USP7 Inhibitor with In Vivo Antileukemic Activity. J.Med.Chem., 69:12502-12518, 2026 Cited by PubMed 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 (). Its pharmacokinetic profile in mice and preliminary safety assessments of the molecule encouraged us to use OAT-4828 as a tool compound for investigations. was well-tolerated in mice, demonstrating significant antileukemic activity in a syngeneic model of B-cell derived non-Hodgkin lymphoma. PubMed: 42090583DOI: 10.1021/acs.jmedchem.6c00407 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.99 Å) |
Structure validation
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