Journal
NATURE CHEMICAL BIOLOGY
Volume 16, Issue 11, Pages 1199-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41589-020-0594-x
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Funding
- Austrian Academy of Sciences
- European Research Council (ERC) under the European Union [851478, 666068]
- Austrian Science Fund (FWF) [P32125-B, P30271-B28]
- Marie Sklodowska-Curie postdoctoral fellowship [796010]
- European Union [765445]
- Human Frontier Science Program (HFSP Long-Term Fellowship) [LT000210/2014]
- European Molecular Biology Organization (EMBO) [ALTF 761-849 2016]
- Novartis Research Foundation
- Austrian Science Fund (FWF) [P32125, P30271] Funding Source: Austrian Science Fund (FWF)
- European Research Council (ERC) [851478, 666068] Funding Source: European Research Council (ERC)
- Marie Curie Actions (MSCA) [796010] Funding Source: Marie Curie Actions (MSCA)
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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.
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