Abstract
USP7 has been recognized as a potential target for the treatment of hematologic malignancies by stabilizing multiple cancer-relevant proteins. Nevertheless, drug-like USP7 inhibitors are still lacking. Herein, compound J21 (USP7 IC50: 41.35 ± 2.16 nM) was discovered based on the structure of L55 and its co-crystal complex with USP7. Additionally, J21 exhibited greater metabolic stability (T1/2: 1.25 h, Cmax: 394.1 ± 48.3 ng/mL, and AUC0-t: 597.8 ± 44.8 ng/mL∙h) compared to L55. These findings may further pave the way for the development of USP7 inhibitors for the treatment of hematologic malignancies.
Copyright © 2024 Elsevier Inc. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Dose-Response Relationship, Drug
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Drug Discovery
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Hematologic Neoplasms / drug therapy
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Hematologic Neoplasms / pathology
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Humans
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Molecular Docking Simulation
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Molecular Structure
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Piperidones / chemical synthesis
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Piperidones / chemistry
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Piperidones / pharmacology
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Structure-Activity Relationship
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Ubiquitin-Specific Peptidase 7* / antagonists & inhibitors
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Ubiquitin-Specific Peptidase 7* / metabolism
Substances
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Ubiquitin-Specific Peptidase 7
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USP7 protein, human
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Antineoplastic Agents
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Piperidones
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Protease Inhibitors