Native mass spectrometry can effectively predict PROTAC efficacy

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Beveridge, Rebecca and Kessler, Dirk and Rumpel, Klaus and Ettmayer, Peter and Meinhart, Anton and Clausen, Tim (2020) Native mass spectrometry can effectively predict PROTAC efficacy. ACS Central Science, 6 (7). pp. 1223-1230. ISSN 2374-7951 (https://doi.org/10.1021/acscentsci.0c00049)

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Abstract

Protein degraders, also known as proteolysis targeting chimeras (PROTACs), are bifunctional small molecules that promote cellular degradation of a protein of interest (POI). PROTACs act as molecular mediators, bringing an E3 ligase and a POI into proximity, thus promoting ubiquitination and degradation of the targeted POI. Despite their great promise as next-generation pharmaceutical drugs, the development of new PROTACs is challenged by the complexity of the system, which involves binary and ternary interactions between components. Here, we demonstrate the strength of native mass spectrometry (nMS), a label-free technique, to provide novel insight into PROTAC-mediated protein interactions. We show that nMS can monitor the formation of ternary E3-PROTAC-POI complexes and detect various intermediate species in a single experiment. A unique benefit of the method is its ability to reveal preferentially formed E3-PROTAC-POI combinations in competition experiments with multiple substrate proteins, thereby positioning it as an ideal high-throughput screening strategy during the development of new PROTACs.

ORCID iDs

Beveridge, Rebecca ORCID logoORCID: https://orcid.org/0000-0003-0320-6496, Kessler, Dirk, Rumpel, Klaus, Ettmayer, Peter, Meinhart, Anton and Clausen, Tim;
  • Item type:Article
    ID code:73438
    Dates:
    Date
    Event
    22 July 2020
    Published
    6 July 2020
    Published Online
    6 July 2020
    Accepted
    Notes:This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:04 Aug 2020 12:25
    Last modified:21 Nov 2024 01:18
    URI:https://strathprints.strath.ac.uk/id/eprint/73438
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