Dimerization of a heat shock protein 90 inhibitor enhances inhibitory activity

Org Biomol Chem. 2014 Feb 7;12(5):765-73. doi: 10.1039/c3ob41722k. Epub 2013 Dec 10.

Abstract

Heat shock protein 90 (hsp90) accounts for 1-2% of the total proteins in normal cells and it functions as a dimer. Hsp90 behaves as a molecular chaperone that folds, assembles, and stabilizes client proteins. We have developed a novel hsp90 inhibitor, and herein we describe the synthesis and biological activity of the dimerized variant of this inhibitor. Tethering a monomer inhibitor together produced a dimerized compound that more effectively inhibits hsp90 over the monomer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dimerization*
  • Drug Design
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Macrocyclic Compounds / chemistry*
  • Macrocyclic Compounds / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Polyethylene Glycols / chemistry
  • Protein Refolding / drug effects
  • Solubility

Substances

  • HSP90 Heat-Shock Proteins
  • Macrocyclic Compounds
  • Polyethylene Glycols