Descrizione del progetto
Le colle molecolari inducono la degradazione delle proteine bersaglio tramite il legame cooperativo alle ligasi E3
La recente scoperta di (degradatori proteici mirati o PROTAC), che sono molecole sintetiche che reclutano proteine bersaglio a una ligasi ubiquitina per l’ubiquitinazione e la conseguente degradazione, ha dimostrato come le molecole progettate razionalmente consentono il targeting di un substrato proteico dannoso. Il progetto Glue2Degrade, finanziato dall’UE, mira a trasformare il targeting proteico in generale, sulla base dell’ipotesi secondo cui le colle molecolari (MG), piccole molecole che degradano le proteine bersaglio tramite il legame cooperativo alle ligasi E3, sono molto più diffuse del previsto. I ricercatori identificheranno nuove MG e le loro ligasi E3 tramite strategie di scoperta fenotipica e un canale genetico chimico ortogonale. I meccanismi delle nuove MG saranno studiati utilizzando proteomica e ottimizzazione chimica. Il successo di Glue2Degrade farà progredire il potenziale per lo sviluppo terapeutico di degradatori chimici specifici per tipo di cellula, di tessuto e di cancro per proteine farmacoresistenti.
Obiettivo
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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Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
1090 Wien
Austria