Label-free in situ monitoring of histone deacetylase drug target engagement by matrix-assisted laser desorption ionization-mass spectrometry biotyping and imaging

Anal Chem. 2014 May 20;86(10):4642-7. doi: 10.1021/ac500038j. Epub 2014 Mar 11.

Abstract

Measurements of target activation in cells or tissues are key indicators of efficacy during drug development. In contrast to established methods that require reagents and multiple preprocessing steps, reagent-free in situ analysis of engaged drug targets or target-proximal pharmacodynamic signatures in solid tumors remains challenging. Here, we demonstrate that label-free quantification of histone acetylation-specific mass shifts by matrix-assisted laser desorption ionization (MALDI) mass spectrometry biotyping can be used for measurement of cellular potency of histone deacetylase inhibitors in intact cells. Furthermore, we employ MALDI mass spectrometry imaging of these mass shifts to visualize the spatiotemporal distribution of acetylated histones and thus the tumor-selective pharmacodynamic responses in a mouse model of gastrointestinal cancer. Taken together, our study suggests that the monitoring of drug-induced mass shifts in protein ion intensity fingerprints or images may be a powerful analytical tool in pharmacology and drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells / enzymology
  • Drug Discovery / methods
  • Gastrointestinal Neoplasms / drug therapy
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors / therapeutic use
  • Histone Deacetylases / drug effects*
  • Mice
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Histone Deacetylase Inhibitors
  • Histone Deacetylases