Targeted protein degradation using heterobifunctional degraders (Proteolysis Targeting Chimeras, PROTACs) is becoming an increasingly important medicinal-chemical strategy for modulating pharmacological targets that are not effectively targeted by traditional inhibitors. Based on their mechanism of action, numerous unwanted proteins can be removed from cells. In this thesis, we focused on the development of PROTACs designed to degrade pathological forms of tau protein, a protein that plays a key role in the onset and progression of Alzheimer's disease. Successful tau degradation would represent a major step towards the treatment of a disease, for which effective therapeutic approaches are lacking. Chimeric tau degraders have already been developed, but they are ineffective due limited cell permeability. Within the thesis, we have, therefore, tried to incorporate crown ethers as linkers in the structure of PROTACs.
We designed three chimeric tau protein degraders containing crown ethers as linkers to connect tau protein ligand and the E3 cereblon ligase ligand. We also synthesized a previously described tau degrader with a linear linker, which served as a comparison compound. We used aza-crown ethers of different sizes for linkers, i.e. 12-crown-4, 15-crown-5, and 18-crown-6. We determined the physicochemical properties of all heterobifunctional molecules and determined that such linkers improved the permeability of PROTACs. In addition, the compounds were also evaluated in a selected cell line for their ability to degrade the tau protein. The crown ether-based compounds showed efficient degradation of the target protein inside the cells, thus highlighting the potential of crown ethers to improve the overall efficacy of PROTACs.
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