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Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM

Author

Listed:
  • Nicholas C. K. Valerie

    (Karolinska University Hospital)

  • Kumar Sanjiv

    (Karolinska Institutet)

  • Oliver Mortusewicz

    (Karolinska Institutet)

  • Si Min Zhang

    (Karolinska Institutet)

  • Seher Alam

    (Karolinska University Hospital)

  • Maria J. Pires

    (Karolinska University Hospital)

  • Hannah Stigsdotter

    (Karolinska Institutet)

  • Azita Rasti

    (Karolinska Institutet)

  • Marie-France Langelier

    (Université de Montréal)

  • Daniel Rehling

    (Stockholm University)

  • Adam Throup

    (Karolinska Institutet)

  • Oryn Purewal-Sidhu

    (Karolinska Institutet)

  • Matthieu Desroses

    (Karolinska Institutet)

  • Jacob Onireti

    (Karolinska University Hospital)

  • Prasad Wakchaure

    (Karolinska Institutet)

  • Ingrid Almlöf

    (Karolinska Institutet)

  • Johan Boström

    (Karolinska University Hospital)

  • Luka Bevc

    (Karolinska Institutet)

  • Giorgia Benzi

    (Karolinska Institutet)

  • Pål Stenmark

    (Stockholm University)

  • John M. Pascal

    (Université de Montréal)

  • Thomas Helleday

    (Karolinska Institutet)

  • Brent D. G. Page

    (Karolinska Institutet
    University of British Columbia)

  • Mikael Altun

    (Karolinska University Hospital)

Abstract

Cellular target engagement technologies enable quantification of intracellular drug binding; however, simultaneous assessment of drug-associated phenotypes has proven challenging. Here, we present cellular target engagement by accumulation of mutant as a platform that can concomitantly evaluate drug-target interactions and phenotypic responses using conditionally stabilized drug biosensors. We observe that drug-responsive proteotypes are prevalent among reported mutants of known drug targets. Compatible mutants appear to follow structural and biophysical logic that permits intra-protein and paralogous expansion of the biosensor pool. We then apply our method to uncouple target engagement from divergent cellular activities of MutT homolog 1 (MTH1) inhibitors, dissect Nudix hydrolase 15 (NUDT15)-associated thiopurine metabolism with the R139C pharmacogenetic variant, and profile the dynamics of poly(ADP-ribose) polymerase 1/2 (PARP1/2) binding and DNA trapping by PARP inhibitors (PARPi). Further, PARP1-derived biosensors facilitated high-throughput screening for PARP1 binders, as well as multimodal ex vivo analysis and non-invasive tracking of PARPi binding in live animals. This approach can facilitate holistic assessment of drug-target engagement by bridging drug binding events and their biological consequences.

Suggested Citation

  • Nicholas C. K. Valerie & Kumar Sanjiv & Oliver Mortusewicz & Si Min Zhang & Seher Alam & Maria J. Pires & Hannah Stigsdotter & Azita Rasti & Marie-France Langelier & Daniel Rehling & Adam Throup & Ory, 2024. "Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54415-7
    DOI: 10.1038/s41467-024-54415-7
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    References listed on IDEAS

    as
    1. Helge Gad & Tobias Koolmeister & Ann-Sofie Jemth & Saeed Eshtad & Sylvain A. Jacques & Cecilia E. Ström & Linda M. Svensson & Niklas Schultz & Thomas Lundbäck & Berglind Osk Einarsdottir & Aljona Sale, 2014. "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool," Nature, Nature, vol. 508(7495), pages 215-221, April.
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    3. Kelvin F. Cho & Taylur P. Ma & Christopher M. Rose & Donald S. Kirkpatrick & Kebing Yu & Robert A. Blake, 2020. "Chaperone mediated detection of small molecule target binding in cells," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. F. Ulrich Hartl & Andreas Bracher & Manajit Hayer-Hartl, 2011. "Molecular chaperones in protein folding and proteostasis," Nature, Nature, vol. 475(7356), pages 324-332, July.
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