Targeting Oncogenic Protein-Protein Interactions by Diversity Oriented Synthesis and Combinatorial Chemistry Approaches

Molecules. 2011 May 27;16(6):4408-27. doi: 10.3390/molecules16064408.

Abstract

We are currently witnessing a decline in the development of efficient new anticancer drugs, despite the salient efforts made on all fronts of cancer drug discovery. This trend presumably relates to the substantial heterogeneity and the inherent biological complexity of cancer, which hinder drug development success. Protein-protein interactions (PPIs) are key players in numerous cellular processes and aberrant interruption of this complex network provides a basis for various disease states, including cancer. Thus, it is now believed that cancer drug discovery, in addition to the design of single-targeted bioactive compounds, should also incorporate diversity-oriented synthesis (DOS) and other combinatorial strategies in order to exploit the ability of multi-functional scaffolds to modulate multiple protein-protein interactions (biological hubs). Throughout the review, we highlight the chemistry driven approaches to access diversity space for the discovery of small molecules that disrupt oncogenic PPIs, namely the p53-Mdm2, Bcl-2/Bcl-xL-BH3, Myc-Max, and p53-Mdmx/Mdm2 interactions.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomimetics
  • Drug Design*
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Oncogene Proteins / antagonists & inhibitors*
  • Oncogene Proteins / metabolism*
  • Protein Binding / drug effects
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use

Substances

  • Antineoplastic Agents
  • Oncogene Proteins
  • Small Molecule Libraries