A novel drug discovery strategy: mechanistic investigation of an enantiomeric antitumor agent targeting dual p53 and NF-κB pathways

Oncotarget. 2014 Nov 15;5(21):10830-9. doi: 10.18632/oncotarget.2521.

Abstract

The p53 and nuclear factor κB (NF-κB) pathways play crucial roles in human cancer development. Simultaneous targeting of both pathways is an attractive therapeutic strategy against cancer. In this study, we report an antitumor molecule that bears a pyrrolo[3,4-c]pyrazole scaffold and functions as an enantiomeric inhibitor against both the p53-MDM2 interaction and the NF-κB activation. It is a first-in-class enantiomeric inhibitor with dual efficacy for cancer therapy. Synergistic effect was observed in vitro and in vivo. Docking and molecular dynamics simulation studies further provided insights into the nature of stereoselectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Drug Discovery*
  • Drug Screening Assays, Antitumor
  • Flow Cytometry
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyrrolidinones / chemical synthesis
  • Pyrrolidinones / pharmacology*
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • 5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-1-(4-fluorobenzyl)-3-phenyl-4,5-dihydropyrrolo(3,4-c)pyrazol-6(1H)-one
  • Antineoplastic Agents
  • NF-kappa B
  • Pyrazoles
  • Pyrrolidinones
  • Tumor Suppressor Protein p53
  • pyrazole
  • Proto-Oncogene Proteins c-mdm2