Novel inhibitors of heat shock protein Hsp70-mediated luciferase refolding that bind to DnaJ

Bioorg Med Chem. 2012 Jun 1;20(11):3609-14. doi: 10.1016/j.bmc.2012.03.067. Epub 2012 Apr 11.

Abstract

Inhibitors of both heat shock proteins Hsp90 and Hsp70 have been identified in assays measuring luciferase refolding containing rabbit reticulocyte lysate or purified chaperone components. Here, we report the discovery of a series of phenoxy-N-arylacetamides that disrupt Hsp70-mediated luciferase refolding by binding to DnaJ, the bacterial homolog of human Hsp40. Inhibitor characterization experiments demonstrated negative cooperativity with respect to DnaJ and luciferase concentration, but varying the concentration of ATP had no effect on potency. Thermal shift analysis suggested a direct interaction with DnaJ, but not with Hsp70. These compounds may be useful tools for studying DnaJ/Hsp40 in various cellular processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemistry*
  • Acetamides / pharmacology*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Drug Evaluation, Preclinical
  • Escherichia coli Proteins / metabolism*
  • HSP40 Heat-Shock Proteins / metabolism*
  • HSP70 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Luciferases / chemistry*
  • Luciferases / metabolism*
  • Protein Folding
  • Rabbits

Substances

  • Acetamides
  • DnaJ protein, E coli
  • Escherichia coli Proteins
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Adenosine Triphosphate
  • Luciferases