Chimera molecule: Russian scientists develop compounds to fight cancer

Russian scientists together with their foreign colleagues have synthesized a line of compounds capable of starting the process of destruction of proteins critical for cancer cells, Russian Science Foundation reported, within the framework of a grant of which the study was conducted. The article of scientists was published in the European Journal of Medicinal Chemistry.

Scientists from St. Petersburg State University, Immanuel Kant Baltic Federal University (Kaliningrad), Togliatti State University together with foreign colleagues have developed non-toxic to healthy tissues compounds that can inhibit the activity of malignant cells. Scientists do not exclude that the obtained substances may become the basis for anti-cancer drugs.

The molecular method of fighting cancer is considered one of the most promising. The essence of the method consists in selective destruction of special proteins, vital for cancerous cells functioning.

For this purpose scientists involve the natural mechanism of intracellular cleaning from damaged proteins. Normally, such proteins that can disrupt normal cell function are detected by a special enzyme - ubiquitinase. It attaches another protein to the protein chain - ubiquitin, which becomes a "black mark" for it. Such "marked" protein molecule is rapidly destroyed by special cell organelles - proteasomes.

The idea to use this mechanism to destroy specific proteins of cancer cells emerged in the scientific community back in the early 2000s. Its essence is to combine the enzyme ubiquitinase with the protein to be destroyed with the help of a mediator molecule. The resulting structure is referred to by chemists as a chimeric molecule. The substance that serves as the "coupling" between the enzyme and the protein is called a "ligand," and the entire technology for targeted protein destruction is called PROTAC (PROteolysis Targeting Chimeras).

"These days, billions of dollars are invested in the development of drugs based on chimeric molecules, and almost every major pharmaceutical company wants them in its portfolio. Chimeric constructs of this type are the perfect "killer," because they can be made to fit almost any desired target protein. At the same time, they work in the cell in extremely low concentrations, which helps avoid side effects," Mikhail Krasavin, Doctor of Chemistry, Head of the Laboratory of Synthesis of Bioactive Small Molecules at St. Petersburg State University, told RT.

To date, molecules of already known immunomodulatory drugs - thalidomide and its close analogues - most often act as a "bridge" for protein binding. However, the use of these substances by pregnant women led to severe developmental disorders in children.

Russian scientists, together with foreign colleagues, have found an alternative to potentially dangerous compounds. Chemists have synthesized 20 different molecules based on glutarimide, an organic nitrogen-containing substance that is nontoxic and willingly binds to enzyme and protein inside the cell. Glutarimide is already used in pharmacology as a component of drugs with sedative and psychostimulant effects.

The authors of the work tested the obtained molecules in vitro in the course of experiments on living cancer cells. Compounds containing sulfur showed the best results: they were two times more effective in binding to the enzyme and target protein than their existing analogs. The new molecules were able to inhibit the activity of bone marrow cancer cells without causing a toxic effect.

According to the scientists, the resulting compounds could become the basis for a number of anticancer drugs in the future.

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