Russian chemists have created molecular constructions based on the organic substance glutarimide, which makes it possible to send the proteins necessary for the division and growth of tumour cells for destruction. The proposed system helps a special 'killer' molecule find the harmful protein and deliver it to the site of degradation. Experiments have proven that the proposed substances inhibit the growth of myeloma cells - bone marrow cancer cells - as well as having no toxic effect. Therefore they are  promising as the basis for drugs to fight cancer. The results of the study, supported by a grant from the Russian Science Foundation (RSF), are published in the European Journal of Medical Chemistry.

 Cancer is one of the leading causes of death in the world. According to WHO statistics, it takes the lives of almost 10 million people a year, so the development of drugs against the cancer is an extremely important direction in medicine. There are different ways to fight tumours, one of the newest and most promising is to use molecular methods to remove specific proteins necessary for cancer cells to grow and multiply. This can be helped by "killer" molecules, which send tumour proteins to special destructive complexes - proteasomes. Proteasomes are present in all animal cells and they are used to break down malfunctioning or defective proteins. Special enzymes - ubiquitinases, one of which is Cereblon, help "guide" them to the site of destruction. So if Cereblon targets proteins that are specific and vital to cancer cells, it will successfully tag them with ubiquitin - a kind of "black mark" - and send them to degrade, and the tumour will stop growing.

Scientists have already developed several systems that can send tumour proteins to degrade. These are molecules made up of three parts: a site that binds to the protein to be destroyed, a linker, or a junction bridge, and a site that recognises the protein. When both components (unwanted protein and Sebrlon) are attached to the molecule, the unwanted protein is "black-tagged" and goes to the proteasome. However, in existing drugs, the site that binds Cereblon is quite toxic, so this treatment may lead to severe side-effects.

Russian scientists with foreign colleagues have proposed to synthesize molecules for degradation of tumor and other proteins based on glutarimide, an organic nitrogen-containing compound that readily binds to Cereblon protein and has no toxic effect. On its basis, the authors have obtained 20 complex molecules, differing in small functional groups, which give the substance a particular charge. It turned out that among them, the compound containing sulfur had the greatest affinity to the protein Cereblon: they were twice as effective in binding to the protein "killer" than their existing analogs.

 The authors then treated bone marrow cancer cell cultures of myeloma cells with the best 'candidate' substances. The experiment showed that the sulphur-containing glutarimide-based compounds inhibited their division. This confirms that these molecules can be used in the development of new types of chimeric drugs to degrade almost any proteins without causing toxic effects.

These days, billions of dollars are invested in drug development based on 'chimeric' molecules, and almost every major pharmaceutical company wants them in its portfolio. Chimeric constructs of this type are the "perfect killer", as they can be made to fit almost any desired target protein. At the same time, they work in extremely low concentrations in the cell, which helps avoid side effects. In the future, they will study the anticancer effect of the molecules we obtained in more detail to find out why compounds containing sulphur are the most active.t