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

Almqvist, Helena (författare)
Karolinska Institutet,Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology
Axelsson, Hanna (författare)
Karolinska Institutet,Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology
Jafari, Rozbeh (författare)
Karolinska Institutet,Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet
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Dan, Chen (författare)
School of Biological Sciences, Nanyang Technological University
Mateus, André (författare)
Uppsala universitet,Institutionen för farmaci
Haraldsson, Martin (författare)
Karolinska Institutet,Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology
Larsson, Andreas (författare)
School of Biological Sciences, Nanyang Technological University
Martinez-Molina, Daniel (författare)
Karolinska Institutet,Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet
Artursson, Per (författare)
Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
Lundbäck, Thomas (författare)
Karolinska Institutet,Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology
Nordlund, Pär (författare)
Karolinska Institutet,Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet
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 (creator_code:org_t)
2016-03-24
2016
Engelska.
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
Relaterad länk:
https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
https://www.nature.c...
https://urn.kb.se/re...
https://doi.org/10.1...
http://kipublication...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)

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