Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic

Bioorg Med Chem Lett. 2013 May 1;23(9):2480-5. doi: 10.1016/j.bmcl.2013.03.034. Epub 2013 Mar 16.

Abstract

A growing number of the elements identified in intracellular signaling events that affect cell growth and transformation are proteins that physically interact with each other via domains or specifically recognized amino acid sequences. Some of these intracellular protein-protein interactions are attractive targets for anticancer targeted therapy, but progress in this field has been compromised by the paucity of compounds with suitable biological profiles and pharmacological properties. This Letter covers salient achievements in the identification and development of inhibitors of the p53-hdm2 protein-protein interaction, and highlights different screening techniques and structure-based design approaches that may be brought to bear on the discovery and development of inhibitors of other therapeutically relevant intracellular protein-protein interactions.

MeSH terms

  • Binding Sites
  • Drug Design
  • HCT116 Cells
  • Humans
  • Imidazolines / chemical synthesis
  • Imidazolines / chemistry
  • Imidazolines / pharmacology
  • Molecular Docking Simulation
  • Piperidines / chemistry
  • Protein Binding
  • Protein Interaction Domains and Motifs / drug effects
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / antagonists & inhibitors*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Imidazolines
  • Piperidines
  • Tumor Suppressor Protein p53
  • piperidine
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2