Project description
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.
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.
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Funding Scheme
ERC-STG - Starting GrantHost institution
1090 Wien
Austria