Discovery of N-Benzylpiperidinol derivatives as USP7 inhibitors against Hematology

Bioorg Chem. 2024 Dec:153:107807. doi: 10.1016/j.bioorg.2024.107807. Epub 2024 Sep 12.

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.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Hematologic Neoplasms / drug therapy
  • Hematologic Neoplasms / pathology
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Piperidones / chemical synthesis
  • Piperidones / chemistry
  • Piperidones / pharmacology
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Ubiquitin-Specific Peptidase 7* / antagonists & inhibitors
  • Ubiquitin-Specific Peptidase 7* / metabolism

Substances

  • Ubiquitin-Specific Peptidase 7
  • USP7 protein, human
  • Antineoplastic Agents
  • Piperidones
  • Protease Inhibitors