Native mass spectrometry can effectively predict PROTAC efficacy [article]

Rebecca Beveridge, Dirk Kessler, Klaus Rumpel, Peter Ettmayer, Anton Meinhart, Tim Clausen
2019 biorxiv/medrxiv   pre-print
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 [1–3]. 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
more » ... e, 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.
doi:10.1101/851980 fatcat:yrd6rdn2v5clhorchfjvafgz7y