Identification of the first non-peptidic small molecule inhibitor of the c-Abl/14-3-3 protein-protein interactions able to drive sensitive and Imatinib-resistant leukemia cells to apoptosis

Bioorg Med Chem Lett. 2010 Oct 15;20(20):6133-7. doi: 10.1016/j.bmcl.2010.08.019. Epub 2010 Aug 8.

Abstract

An in silico structure-based ligand design approach resulted in the identification of the first non-peptidic small molecule able to inhibit protein-protein interactions between 14-3-3 and c-Abl. This compound shows an anti-proliferative effect on human leukemia cells either sensitive or resistant to Imatinib, in consequence of the T315I mutation. It also mediates c-Abl release from 14-3-3 in a way similar to that found in response to Imatinib treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / antagonists & inhibitors*
  • 14-3-3 Proteins / metabolism
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Benzamides
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Models, Molecular
  • Piperazines / pharmacology
  • Protein Binding
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrimidines / pharmacology
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*

Substances

  • 14-3-3 Proteins
  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Small Molecule Libraries
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-abl