Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Eur J Med Chem. 2020 Aug 15:200:112338. doi: 10.1016/j.ejmech.2020.112338. Epub 2020 May 18.


Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.

Keywords: Acute myeloid leukemia; BRPF1; Bromodomain; Dual targeting inhibitors; Epigenetics; HDAC6; HDAC8; Hydroxamic acids.

MeSH terms

  • Acetylation / drug effects
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Drug Design*
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases
  • Humans
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Repressor Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • BRPF1 protein, human
  • DNA-Binding Proteins
  • Histone Deacetylase Inhibitors
  • Repressor Proteins
  • HDAC6 protein, human
  • HDAC8 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases