A promising therapeutic approach in the development of medicinal agents is modulation of protein activity. In the last 20 years, the pharmaceutical industry has mainly focused on the development of small molecules, including enzyme inhibitors which can be used for target modulation. Small-molecule inhibitors exert their action through ''occupancy-driven'' model, which limits their use in targeting ''undruggable'' proteome. In addition, their maximum effect often requires a high systemic exposure which can lead to the occurrence of unwanted side effects. Strategies based on ''event-driven'' pharmacology offer more promising approaches for targeting proteins compared to traditional small-molecule inhibitors. An example of this approach are PROTACs (proteolysis-targeting chimeras), which consist of three parts: a ligand for binding to the target protein, a ligand for binding to the E3 ligase and a linker. These compounds exploit the ubiquitin proteasome pathway by inducing degradation of the target protein and thus completely removing it. PROTACs were first described by Crews and coworkers in 2001, and to date numerous compounds have been developed. These target more than 50 different proteins, many of which play an important role in the development of cancer, viral infections, autoimmune and neurodegenerative diseases. However, despite their great characteristics the use of PROTACs is mainly limited by their low cell permeability. The PROTACs methodology it is still far from fully developed. It shows a great potential especially in the treatment of cancer, as PROTACs are also capable of depleting rapidly mutatig and resistance-prone targets.
One target that is often involved in the development of various forms of cancer (such as multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia, breast cancer and lung cancer) is Bcl-2 protein. In cases of its overexpression apoptosis in blocked, which causes resistance to treatment with classical small-molecule inhibitors. Therefore, Bcl-2 represents an appropriate target for the treatment of Bcl-2 dependent cancers using PROTACs. In this work we synthesized a ligand for IAP (an E3 ligase), which we connected with two different linkers to a ligand for Bcl-2 to obtain the designed PROTAC molecules. Preliminary cell-based evaluations showed no Bcl-2 degradation under selected treatment conditions. Future cellular evaluation should encompass a wider variety of cancer cells and more treatment conditions such as prolonged treatment time and different concentration range.
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