Cancer is one of the most important global health problems due to its complex pathological nature, which is usually caused by genetic mutations within cells. Mutations can affect proto-oncogenes, tumor suppressor genes, and also regulatory pathways of programmed cell death (i.e. apoptosis), ultimately leading to uncontrolled cell proliferation and invasive tumor spread. Current cancer treatments include surgery, radiotherapy, chemotherapy and novel targeted therapy. Although conventional chemotherapy is effective against rapidly dividing cells, it is not specific to cancer cells and therefore often causes severe side effects. This highlights the need for more selective targeted therapies with fewer side effects. A promising approach in this direction is targeted protein degradation using PROTACs or chimeric degraders, which exploit the ubiquitin-proteasome system to eliminate unwanted proteins from cells, including some key regulators of carcinogenesis.
A crucial factor in cancer development is the ability of malignant cells to evade apoptosis, allowing them to survive despite genetic mutations. The Bcl-2 protein family plays a central role in this process. Within this family, the most problematic is the overexpression of the anti-apoptotic Bcl-2 protein, which can be found in certain types of hematologic cancers. Selective degradation of Bcl-2 with PROTACs could enhance treatment results while reducing the side effects associated either with existing therapies or with previously developed Bcl-2 chimeric degraders, which are non-selective.
This master's thesis focuses on the design and synthesis of novel PROTAC molecules for potential Bcl-2 degradation. For this purpose, a subset of chimeric degraders was synthesized, which consisted of a Bcl-2 binder (Nap-1), linkers of different chemical nature, and a ligand for the VHL E3 ligase. The impact of these synthesized PROTAC molecules on Bcl-2 degradation in HeLa cells was evaluated using Western blot analysis and fluorescence intensity measurements. While the results were suboptimal, this research contributes to a better understanding of the chemical space needed for selective Bcl-2 degradation and provides a possible starting point for further development of PROTAC-based therapies in future cancer treatment.
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