Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors

J Med Chem. 2016 Feb 25;59(4):1613-33. doi: 10.1021/acs.jmedchem.5b01632. Epub 2016 Jan 7.


Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.

MeSH terms

  • Depsipeptides / chemical synthesis
  • Depsipeptides / chemistry*
  • Depsipeptides / pharmacology*
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism*
  • Humans
  • Molecular Docking Simulation
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology*


  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Protein Isoforms
  • Thiazoles
  • largazole
  • Histone Deacetylases