Journal article
Rational discovery of molecular glue degraders via scalable chemical profiling.
- Mayor-Ruiz C CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Bauer S CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Brand M CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Kozicka Z FMI Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
- Siklos M CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Imrichova H CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Kaltheuner IH Institute of Structural Biology, University of Bonn, Bonn, Germany.
- Hahn E CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Seiler K CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Koren A CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Petzold G FMI Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
- Fellner M Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
- Bock C CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Müller AC CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Zuber J Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
- Geyer M Institute of Structural Biology, University of Bonn, Bonn, Germany.
- Thomä NH FMI Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
- Kubicek S CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
- Winter GE CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gwinter@cemm.oeaw.ac.at.
- 2020-08-05
Published in:
- Nature chemical biology. - 2020
English
Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts. Here, we describe a scalable strategy toward glue degrader discovery that is based on chemical screening in hyponeddylated cells coupled to a multi-omics target deconvolution campaign. This approach led us to identify compounds that induce ubiquitination and degradation of cyclin K by prompting an interaction of CDK12-cyclin K with a CRL4B ligase complex. Notably, this interaction is independent of a dedicated substrate receptor, thus functionally segregating this mechanism from all described degraders. Collectively, our data outline a versatile and broadly applicable strategy to identify degraders with nonobvious mechanisms and thus empower future drug discovery efforts.
- Language
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- English
- Open access status
- closed
- Identifiers
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- DOI 10.1038/s41589-020-0594-x
- PMID 32747809
- Persistent URL
- https://sonar.ch/global/documents/98601
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