Project description DEENESFRITPL 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. Show the project objective Hide the project objective Objective Traditional drug design relies on inhibition of enzymes or receptors with accessible hydrophobic pockets. The concept of proteolysis targeting chimeras (PROTACs) promised to overcome this limitation. Following our discovery of the first PROTAC that induced selective protein degradation in vivo, this technology has seen a boost in academia and industry. Despite global research efforts, advances are so far incremental: (i) most focus is on degrading targets that can be liganded and are druggable with conventional inhibitors; (ii) currently, only 3 out of 600 E3 ligases can be exploited. Glue2Degrade aims to transform the pharmacologically targetable space of the proteome. The project is built on the hypothesis that molecular glues (MGs), non-chimeric small molecules that degrade target proteins by inducing cooperative binding to E3 ligases, are much more prevalent than anticipated. Lenalidomide and related immunomodulatory drugs (IMiDs) are prime examples of the potential of MGs. Without a specific targeting moiety, IMiDs induce cooperative binding of the E3 ligase CRBN to undruggable proteins like IKZF1/3, thereby inducing their degradation. However, no technologies exist to rationally develop MGs that hijack other E3 ligases. ERC-funding would allow us to address this limitation. Based on data generated in my laboratory, we will systematically identify novel MGs and their E3 ligases by innovating (i) phenotypic discovery strategies, and (ii) an orthogonal chemical genetics pipeline. To elucidate the mechanisms of novel MGs, we will (iii) conduct target identification via unbiased proteomics followed by (iv) chemical optimization and initial translational characterization. Glue2Degrade, if successful, will transform the engageable E3 space and identify novel MGs, thereby opening up the potential for therapeutic development of cell-, tissue-, and cancer-type specific chemical degraders for undruggable proteins. Fields of science natural sciencesbiological sciencesgeneticsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsmedical and health sciencesbasic medicinemedicinal chemistrynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-STG - ERC Starting Grant Call for proposal ERC-2019-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Coordinator CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH Net EU contribution € 1 331 340,00 Address Lazarettgasse 14 akh bt 25.3 1090 Wien Austria See on map Region Ostösterreich Wien Wien Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH Austria Net EU contribution € 1 331 340,00 Address Lazarettgasse 14 akh bt 25.3 1090 Wien See on map Region Ostösterreich Wien Wien Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
