Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups

J Med Chem. 2020 Sep 24;63(18):10339-10351. doi: 10.1021/acs.jmedchem.9b01888. Epub 2020 Sep 1.

Abstract

Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Bortezomib / pharmacology
  • Cell Line, Tumor
  • Daunorubicin / pharmacology
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Epirubicin / pharmacology
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis
  • Tetrazoles / metabolism
  • Tetrazoles / pharmacology*

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Tetrazoles
  • Epirubicin
  • Bortezomib
  • HDAC6 protein, human
  • Hdac6 protein, mouse
  • Histone Deacetylase 6
  • Daunorubicin