FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases

Cancer Res. 2002 Sep 1;62(17):4916-21.


FK228 is a histone deacetylase (HDAC) inhibitor, the molecular mechanism of inhibition of which has been unknown. Here we show that reduction of an intramolecular disulfide bond of FK228 greatly enhanced its inhibitory activity and that the disulfide bond was rapidly reduced in cells by cellular reducing activity involving glutathione. Computer modeling suggests that one of the sulfhydryl groups of the reduced form of FK228 (redFK) interacts with the active-site zinc, preventing the access of the substrate. HDAC1 and HDAC2 were more strongly inhibited by redFK than HDAC4 and HDAC6. redFK was less active than FK228 in inhibiting in vivo HDAC activity, due to rapid inactivation in medium and serum. Thus, FK228 serves as a stable prodrug to inhibit class I enzymes and is activated by reduction after uptake into the cells. The glutathione-mediated activation also implicates its clinical usefulness for counteracting glutathione-mediated drug resistance in chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology*
  • Antibiotics, Antineoplastic / chemistry
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Antibiotics, Antineoplastic / pharmacology*
  • Binding Sites
  • Biotransformation
  • Depsipeptides*
  • Drug Stability
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Glutathione / metabolism
  • HeLa Cells
  • Histone Deacetylase Inhibitors*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Models, Molecular
  • Molecular Sequence Data
  • Oxidation-Reduction
  • Peptides, Cyclic*
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology*
  • Zinc / metabolism


  • Anti-Bacterial Agents
  • Antibiotics, Antineoplastic
  • Depsipeptides
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Isoenzymes
  • Peptides, Cyclic
  • Prodrugs
  • romidepsin
  • Glutathione
  • Zinc