An international team of researchers led by the Universities of Bonn and Ulm has investigated how a cell's own “protein shredder” can be specifically programmed to fight cancer. In their study, the scientists were able to demonstrate the breakdown of proteins that are excessively active in breast cancer, for example. The results have been published in the renowned "Chemical Science" journal.
Cells continuously produce proteins so that they can perform their tasks in the body. Those protein molecules that are no longer needed are given a kind of "disposal sticker". All proteins with such a label are then shredded and recycled by a cell shredder, the proteasome.
For some years now, researchers have been trying to use this mechanism specifically to fight diseases such as cancer. Because tumor cells also need certain proteins. If you could put a degradation label on them, the proteasome would inevitably shred them. This would inhibit the growth of the cancer cell.
In fact, this approach has already proven effective in the test tube. Scientists use so-called PROTACs (the abbreviation stands for "proteolysis targeting chimeras"). "The production of these active ingredients is very complicated," explains Prof. Dr. Michael Gütschow from the Pharmaceutical Institute of the University of Bonn. "We examined which strategies are promising and how particularly effective PROTACs can be tailored to a certain extent."
PROTACs are molecular hermaphrodites: On the one hand, they consist of a part of the molecule that docks onto the cancer protein. On the other hand, they contain a structure that can bind to labeling enzymes. Both units are connected by a kind of arm. PROTACs bring target protein and labeling machine together and ensure that the harmful protein receives the disposal label.
"We have synthesized many molecules, among other things to find out what structure and length the arm must have in order for the protein to be labeled as effectively as possible," explains Christian Steinebach from the Pharmaceutical Institute at the University of Bonn. The scientists also optimized another point of the PROTACs. Each cell has dozens of different labeling enzymes called ubiquitin ligases. Not every one of them works equally well with every protein. "We have therefore produced and tested various PROTACs for different ligases," emphasizes Dr. Jan Krönke from Ulm University Hospital.
The active ingredients developed are directed against a protein that ensures that cancer cells can reproduce better. The PROTACs now cause the cell's own shredder to destroy the protein. "In experiments with cell cultures, we were able to show that our PROTACs actually significantly reduce the cellular concentration of this protein and effectively suppress the growth of cancer cells," explains Dr. Krönke. "The active ingredients now allow us to study proteins that are important for the tumor in more detail."
The universities of Bonn and Ulm are among the leading institutions in Germany in the young field of PROTAC research. "Our study shows prototypically which techniques can be used to manufacture these substances and optimize them in a targeted manner," says Gütschow. There is great interest in such strategies, as PROTACs are an important source of hope for the treatment of serious diseases.
Reference: Christian Steinebach, Yuen Lam Dora Ng, Izidor Sosič, Chih-Shia Lee, Sirui Chen, Stefanie Lindner, Lan Phuong Vu, Aleša Bricelj, Reza Haschemi, Marius Monschke, Elisabeth Steinwarz, Karl G. Wagner, Gerd Bendas, Ji Luo , Michael Gütschow and Jan Krönke. (2020) Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chemical science. DOI: dx.doi.org/10.1039/d0sc00167h
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