Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening

J Med Chem. 2015 Feb 26;58(4):2036-41. doi: 10.1021/jm501344n. Epub 2015 Feb 17.

Abstract

We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Catalytic Domain / drug effects
  • Cell Proliferation / drug effects
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Injections, Intraperitoneal
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / administration & dosage
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Pyrazoles / administration & dosage
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Proteasome Inhibitors
  • Pyrazoles
  • Small Molecule Libraries
  • pyrazole
  • Proteasome Endopeptidase Complex