Molecular glues induce target protein degradation by cooperative binding to E3 ligases
Recent discovery of the proteolysis-targeting chimeras (PROTACs), which are synthetic molecules recruiting target proteins to a ubiquitin ligase for ubiquitination and subsequent degradation, demonstrated how the rationally designed molecules enable targeting of a harmful protein substrate. The EU-funded project Glue2Degrade aims to transform the protein targeting in general, based on the hypothesis that molecular glues (MGs), small molecules that degrade target proteins through cooperative binding to E3 ligases, are much more prevalent than anticipated. Researchers will identify novel MGs and their E3 ligases by phenotypic discovery strategies and an orthogonal chemical genetics pipeline. The mechanisms of novel MGs will be studied using proteomics and chemical optimisation. Glue2Degrade's success will advance the potential for therapeutic development of cell-, tissue- and cancer-type specific chemical degraders for undruggable proteins.
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