PROTACs

Classical pharmacological inhibitors can only target a small subset of proteins mainly catalytically active enzymes. Therefore, the vast majority of the proteome remains undruggable including transcription factors, receptors or structural proteins. A novel therapeutic strategy to influence all versatile proteins is the marking of proteins for the degradation by the cell’s own ubiquitin-proteasome system. With bifunctional molecules called PROTACs (proteolysis-targeting chimeras) the protein of interest is brought into close proximity with a E3 ubiquitin ligase. Thereby ubiquitin is transferred to the protein and is designated to proteasomal degradation. PROTACs consist of one ligand binding the protein of interest and another ligand specific for an E3 ligase. Those two domains are connected via a linker, which is influencing with its structure, flexibility and length the potency of PROTACs.

PROTACs are the most advance class of proximity-inducing drugs, of which some reached clinical trials mostly for applications in oncology.

Jointly with Prof. Plettenburg (Leibnitz University Hannover) novel PROTACs are designed, synthetized, which are then characterized for its functionality at our institute. In cell-free, basic cell culture and more sophisticated three-dimensional models, PROTACs can be analyzed for their target specificity. The PROTACs can be then tested in different disease models for their efficacy. Based on the functional results, the structure of the PROTACs can be further optimized.

This drug class has the potential to serve as a tool box to target any desired protein and recruiting a specific E3 ligase which will generate tissue specificity in future.