4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor

Bioorg Med Chem Lett. 2013 Nov 1;23(21):6015-8. doi: 10.1016/j.bmcl.2013.08.001. Epub 2013 Aug 11.


This letter describes the mechanism behind the protective effect of 4-phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4-PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of chemical chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the chemical chaperone activity rather than by inhibition of histone deacetylase.

Keywords: 4-phenylbutyric acid (4-PBA); Acetyl histone H3; Chemical chaperone; Endoplasmic reticulum (ER) stress; Histone deacetylase (HDAC).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / drug effects*
  • Cell Line, Tumor
  • Endoplasmic Reticulum Stress / drug effects*
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / pharmacology*
  • Phenylbutyrates / chemistry
  • Phenylbutyrates / pharmacology*
  • Protective Agents / chemistry
  • Protective Agents / pharmacology*
  • Protein Conformation / drug effects


  • Histone Deacetylase Inhibitors
  • Molecular Chaperones
  • Phenylbutyrates
  • Protective Agents
  • 4-phenylbutyric acid