Label-Free in Situ Monitoring of Histone Deacetylase Drug Target Engagement by Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry Biotyping and Imaging

Label-Free in Situ Monitoring of Histone Deacetylase Drug Target Engagement by Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry Biotyping and Imaging

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...

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Bibliographic Details
Published in:Analytical chemistry (Washington) Vol. 86; no. 10; pp. 4642 - 4647
Main Authors: Munteanu, Bogdan, Meyer, Björn, von Reitzenstein, Carolina, Burgermeister, Elke, Bog, Susanne, Pahl, Andreas, Ebert, Matthias P, Hopf, Carsten
Format: Journal Article
Language:English
Published: United States American Chemical Society 20-05-2014
Subjects:
Animals
Biochemistry
Cells - enzymology
Desorption
Drug Discovery - methods
Drugs
Gastric cancer
Gastrointestinal diseases
Gastrointestinal Neoplasms - drug therapy
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylase Inhibitors - therapeutic use
Histone Deacetylases - drug effects
Histones
Imaging
Inhibitors
Lasers
Mass spectrometry
Mice
Monitoring
Pharmacology
R&D
Research & development
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Summary: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 gasterointestinal 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.
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ISSN:0003-2700
1520-6882
DOI:10.1021/ac500038j