Native mass spectrometry can effectively predict PROTAC efficacy

Rebecca Beveridge, Dirk Kessler, Klaus Rumpel, Peter Ettmayer, Anton Meinhart, Tim Clausen

Research output: Working paper

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Protein degraders, also known as proteolysis targeting chimeras (PROTACs), are bifunctional small molecules that bring an E3 ubiquitin ligase and a protein of interest (POI) into proximity, thus promoting ubiquitination and degradation of the targeted POI [1textendash3]. 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.
Original languageEnglish
Place of PublicationCold Spring Harbor, N.Y.
Number of pages16
Publication statusPublished - 25 Nov 2019


  • proteolysis targeting chimeras
  • protein degraders
  • next-generation pharmaceuticals


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