Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors

ChemMedChem. 2020 Jul 3;15(13):1163-1174. doi: 10.1002/cmdc.202000149. Epub 2020 May 13.

Abstract

We report the synthesis and evaluation of a class of selective multitarget agents for the inhibition of HDAC6, HDAC8, and HDAC10. The concept for this study grew out of a structural analysis of the two selective inhibitors Tubastatin A (HDAC6/10) and PCI-34051 (HDAC8), which we recognized share the same N-benzylindole core. Hybridization of the two inhibitor structures resulted in dihydroxamic acids with benzyl-indole and -indazole core motifs. These substances exhibit potent activity against HDAC6, HDAC8, and HDAC10, while retaining selectivity over HDAC1, HDAC2, and HDAC3. The best substance inhibited the viability of the SK-N-BE(2)C neuroblastoma cell line with an IC50 value similar to a combination treatment with Tubastatin A and PCI-34051. This compound class establishes a proof of concept for such hybrid molecules and could serve as a starting point for the further development of enhanced HDAC6/8/10 inhibitors.

Keywords: HDAC10; HDAC8; inhibitors; polypharmacology; targeted therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Molecular Structure
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Repressor Proteins
  • HDAC6 protein, human
  • HDAC8 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases