What question did this study set out to answer?

To establish a biophysical screening approach in living cells that monitors intracellular target binding and correlates compound uptake and activation kinetics using human thymidylate synthase.

March 24, 2016Nature CommunicationsOpen Access

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

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Authors

HAHelena AlmqvistPelago Bioscience (Sweden)HAHanna AxelssonBirdLife International RJRozbeh JafariScience for Life Laboratory

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Implication

Biophysical screening study demonstrates intracellular thymidylate synthase engagement and slow 5-fluorouracil activation in live cells, highlighting a novel platform for target validation.

Key Points

To establish a biophysical screening approach in living cells that monitors intracellular target binding and correlates compound uptake and activation kinetics using human thymidylate synthase.
Screened a compound library using cellular thermal shift assay (CETSA) measurements of intracellular target binding to native human thymidylate synthase in live cells.
Tracked compound uptake and enzymatic processing over time to monitor the intracellular emergence of active metabolites alongside target engagement.
Accurately detected all tested known thymidylate synthase inhibitors and identified novel chemical inhibitor scaffolds.
Identified off-target thymidylate synthase engagement by marketed compounds not previously recognized to inhibit it, including decitabine.
Revealed substantially slower intracellular activation kinetics for 5-fluorouracil relative to nucleoside-based agents.

Cite This Study

Almqvist et al. (2016) studied this question.

synapsesocial.com/papers/6a096dc130285ee4a133fdb5 https://doi.org/10.1038/ncomms11040

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Implication

Biophysical screening study demonstrates intracellular thymidylate synthase engagement and slow 5-fluorouracil activation in live cells, highlighting a novel platform for target validation.

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

Discussion

Member takes

Implication

Key Points

Cite This Study

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

Discussion

Member takes

Implication

Key Points

Cite This Study

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