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Title: CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
Authors: Almqvist, Helena
Axelsson, Hanna
Jafari, Rozbeh
Dan, Chen
Mateus, André
Haraldsson, Martin
Larsson, Andreas
Molina, Daniel Martinez
Artursson, Per
Lundbäck, Thomas
Nordlund, Pär
Keywords: Screening
DRNTU::Science::Biological sciences
Molecular Biophysics
Issue Date: 2016
Source: Almqvist, H., Axelsson, H., Jafari, R., Dan, C., Mateus, A., Haraldsson, M., . . . Nordlund, P. (2016). CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil. Nature Communications, 7, 11040-. doi:10.1038/ncomms11040
Series/Report no.: Nature Communications
Abstract: Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.
DOI: 10.1038/ncomms11040
Rights: © 2016 The Author(s) (Published by Nature Publishing Group). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Fulltext Permission: open
Fulltext Availability: With Fulltext
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