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

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• 作者：Bogdan Munteanu ; Bj枚rn Meyer ; Carolina von Reitzenstein ; Elke Burgermeister ; Susanne Bog ; Andreas Pahl ; Matthias P. Ebert ; Carsten Hopf
• 刊名：Analytical Chemistry
• 出版年：2014
• 出版时间：May 20, 2014
• 年：2014
• 卷：86
• 期：10
• 页码：4642-4647
• 全文大小：383K
• 年卷期：v.86,no.10(May 20, 2014)
• ISSN：1520-6882

文摘

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.