title: Label-free in situ monitoring of histone deacetylase drug target engagement by matrix-assisted laser desorption ionization-mass spectrometry biotyping and imaging.
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.
authors.affiliation: Institute of Medical Technology, University of Heidelberg and Mannheim University of Applied Sciences , ‡Center for Applied Research in Biomedical Mass Spectrometry (ABIMAS), and §Instrumental Analytics and Bioanalytics, Mannheim University of Applied Sciences , Paul-Wittsack-Strasse 10, 68163, Mannheim, Germany.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Munteanu
authors.forename: Björn
authors.initials: B
authors.lastname: Meyer
authors.forename: Carolina
authors.initials: C
authors.lastname: von Reitzenstein
authors.forename: Elke
authors.initials: E
authors.lastname: Burgermeister
authors.forename: Susanne
authors.initials: S
authors.lastname: Bog
authors.forename: Andreas
authors.initials: A
authors.lastname: Pahl
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Ebert
authors.forename: Carsten
authors.initials: C
authors.lastname: Hopf
mesh_terms: D000818:Animals; D002477:Cells / Q000201:enzymology; D055808:Drug Discovery / Q000379:methods; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000187:drug effects*; D051379:Mice; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases