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Rational discovery of molecular glue degraders via scalable chemical profiling
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Rational discovery of molecular glue degraders via scalable chemical profiling
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Journal Article
Rational discovery of molecular glue degraders via scalable chemical profiling
2020
Overview
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.
Chemical profiling in hyponeddylated cells coupled with multi-omics target deconvolution led to the identification of molecular glue degraders of cyclin K that function by inducing proximity between the CRL adaptor DDB1 and a CDK12–cyclin K complex.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Anti-Bacterial Agents - pharmacology
/ Biology
/ Chemistry and Materials Science
/ CRISPR
/ Cyclin-Dependent Kinases - metabolism
/ Dose-Response Relationship, Drug
/ Drug Evaluation, Preclinical
/ Enzymes
/ Glues
/ Humans
/ Kinases
/ Mutation
/ Protein Processing, Post-Translational - drug effects
/ Proteins
/ Retinoblastoma-Binding Protein 7 - metabolism
/ Small Molecule Libraries - chemistry
/ Structure-Activity Relationship
