Syntheses and discovery of a novel class of cinnamic hydroxamates as histone deacetylase inhibitors by multimodality molecular imaging in living subjects

Cancer Res. 2014 Dec 15;74(24):7475-86. doi: 10.1158/0008-5472.CAN-14-0197. Epub 2014 Oct 15.

Abstract

Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays, with further evaluation to inhibit Hsp90(α/β)/p23 interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(α/β)/p23 interactions, UKE-1 myeloid cell proliferation, p21(waf1) upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(α)/p23 reporters relative to carrier control-treated mice as determined by BLI. Small animal (18)F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor.

Publication types

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

MeSH terms

  • Acetylation
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cinnamates / chemical synthesis
  • Cinnamates / isolation & purification
  • Cinnamates / pharmacology
  • Fluorodeoxyglucose F18
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / isolation & purification*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry
  • Humans
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / isolation & purification*
  • Mice
  • Molecular Imaging*
  • Multimodal Imaging*
  • Myeloid Cells / drug effects

Substances

  • Cinnamates
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Fluorodeoxyglucose F18
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases
  • cinnamic acid