CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil

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 t...

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Main Authors: Almqvist, Helena, Axelsson, Hanna, Jafari, Rozbeh, Dan, Chen, Mateus, André, Haraldsson, Martin, Larsson, Andreas, Molina, Daniel Martinez, Artursson, Per, Lundbäck, Thomas, Nordlund, Pär
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2018
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Online Access:https://hdl.handle.net/10356/89820
http://hdl.handle.net/10220/47161
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-898202023-02-28T17:02:18Z CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil Almqvist, Helena Axelsson, Hanna Jafari, Rozbeh Dan, Chen Mateus, André Haraldsson, Martin Larsson, Andreas Molina, Daniel Martinez Artursson, Per Lundbäck, Thomas Nordlund, Pär School of Biological Sciences Screening DRNTU::Science::Biological sciences Molecular Biophysics 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. Published version 2018-12-21T04:25:04Z 2019-12-06T17:34:14Z 2018-12-21T04:25:04Z 2019-12-06T17:34:14Z 2016 Journal Article 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 https://hdl.handle.net/10356/89820 http://hdl.handle.net/10220/47161 10.1038/ncomms11040 27010513 en Nature Communications © 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 http://creativecommons.org/licenses/by/4.0/. 11 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Screening
DRNTU::Science::Biological sciences
Molecular Biophysics
spellingShingle Screening
DRNTU::Science::Biological sciences
Molecular Biophysics
Almqvist, Helena
Axelsson, Hanna
Jafari, Rozbeh
Dan, Chen
Mateus, André
Haraldsson, Martin
Larsson, Andreas
Molina, Daniel Martinez
Artursson, Per
Lundbäck, Thomas
Nordlund, Pär
CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
description 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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Almqvist, Helena
Axelsson, Hanna
Jafari, Rozbeh
Dan, Chen
Mateus, André
Haraldsson, Martin
Larsson, Andreas
Molina, Daniel Martinez
Artursson, Per
Lundbäck, Thomas
Nordlund, Pär
format Article
author Almqvist, Helena
Axelsson, Hanna
Jafari, Rozbeh
Dan, Chen
Mateus, André
Haraldsson, Martin
Larsson, Andreas
Molina, Daniel Martinez
Artursson, Per
Lundbäck, Thomas
Nordlund, Pär
author_sort Almqvist, Helena
title CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
title_short CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
title_full CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
title_fullStr CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
title_full_unstemmed CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
title_sort cetsa screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
publishDate 2018
url https://hdl.handle.net/10356/89820
http://hdl.handle.net/10220/47161
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