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