Georg Winter

Knock out oncogenic drivers and curing kids (KOODAC)

Therapeutic hijacking of E3 Ligases

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.

Innovating Strategies to prompt anti-cancer immunity via targeted protein degradation

Chemical probing and functional characterization of the E3 substrate receptor DCAF15

The targeted degradation of proteins is of utmost importance for the well-being of our cells and thus for the entire organism. Damaged proteins must be recognized and removed to prevent collateral damage. In addition, proteins must be removed in a targeted manner in order to allow the activation, but also the deactivation of cellular signal transduction pathways. Defects in the targeted degradation of proteins can result in diseases such as cancer and neurodegeneration.

The Special Research Program, SFB F79, is funded by the Austrian Science Fund (FWF) with contributions by the German Research Foundation (DFG).

The collaborative research program includes scientists from Max Perutz Labs, University of Vienna, Medical University of Vienna, CeMM, GMI, IMBA and IMP from Vienna as well as IMB in Mainz, who have joined forces to discover mechanism of targeted protein degradation, and how this process can be manipulated.

Mechanisms of protein degradation via hydrophobic tagging

Chemical hijacking KRAS-driven proteolytic networks

ReprogrammAR: Chemical Reprogramming of Autophagy Receptors