Native mass spectrometry can effectively predict PROTAC efficacy

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

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
30 Downloads (Pure)


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.
Original languageEnglish
Pages (from-to)1223-1230
Number of pages8
JournalACS Central Science
Issue number7
Early online date6 Jul 2020
Publication statusPublished - 22 Jul 2020


  • cellular degradation
  • protein of interest (POI)


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