Abnormal function of BCL6 protein is the cause of the development of lymphoma. With the participation of Poles, an international team of scientists discovered the mechanism to eliminate pathogenic proteins. He used a compound that would combine harmful proteins into a long polymer thread and then quickly degrade it.
BCL6 is one of countless proteins in the human body. This is essential for distinguishing blood cells and regulating the role of many other proteins. Too much BCL6 may trigger the tumor formation process and the development of lymphatic system tumors, such as lymphoma. Studies in lymphoma cells and animal models have shown that the inactivation of this protein leads to the disappearance of the disease.
For many years, people have been trying to develop a drug that can reduce “bad” BCL6 levels, but the compounds tested are not effective enough. “The problem is that nowadays, most cancer drugs are called inhibitors that block specific functions of proteins. Unfortunately, only some disease-causing proteins respond to their functions. BCL6 is not one of them.”-From MIT and Mikołaj Słabicki of the Broad College of Harvard University explained that the Dana-Farber Cancer Institute in Boston and the German Cancer Research Center in Heidelberg said.
In the laboratory where he works, he is looking for new ways to inactivate these disease-causing proteins. Blocking these disease-causing proteins with classic inhibitors is ineffective, or even impossible. Such drugs already exist, for example by acting on the principle of “molecular glue”, that is, degrading agents link functional proteins with another protein (called ubiquitin ligase) that makes them harmless . These include, for example, lenalidomide, among others, for the treatment of multiple myeloma and the recently described compound CR8.
Three years ago, the pharmaceutical company Boehringer Ingelheim (Boehringer Ingelheim) searched for a substance that can block the action of the BCL6 protein and analyzed nearly 2 million chemical compounds in its resources. One of the identified compounds is an extremely effective degrader of BCL6 protein. This tiny molecule initiates the process of destroying BCL6, leading to the specific death of cancer cells. However, the exact mechanism of this process is unclear, so it is difficult to refine such compounds for potential treatment.
Therefore, the explanation is sought by researchers led by the professor. Benjamin Ebert and the professor. Eric Fischer of Dana-Farber Cancer Institute. They managed to explain the mysterious mechanism so far, the description of which was published by the prestigious “Nature”. The main authors of this work are: Mikołaj Słabicki (Mikołaj Słabicki), Yin Zongj (Hojong Yoon), and Jonas Koeppel (Jonas Koeppel).
In order to track what happened to the BCL6 protein after the application of the composite degradant, the scientists labeled it with a fluorescent protein that can be seen in cells. Therefore, they noticed that the degradation agent caused aggregates (cell clusters) of BLC6 to form, which disappeared after tens of minutes. Radosław Nowak, a co-author of the Dana-Farber Cancer Institute in Boston, explained: “In the process of studying these aggregates, the results showed that the BCL6 protein first undergoes a polymerization process under the action of a degrading agent. This means that its subsequent molecules will stick together to form a long, polymerized thread.” The researchers also discovered the last part of the puzzle: they discovered a ubiquitin ligase (called SIAH1) that can effectively destroy the polymerized BCL6 protein.
“We have never looked for drugs that can polymerize malfunctioning proteins. Now, we know that things like this are possible-describe Słabicki.-We hope that the same method can be used to remove other proteins. The disorder of this protein can lead to cancer progression-he emphasized .
You can watch an animation explaining its mechanism here. (PAP)
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