Hardly any active ingredient has had such a turbulent history as thalidomide. The molecule is the central ingredient of Contergan, which was approved in many countries in the 1950s as a sedative and sleeping pill. But it soon became apparent that pregnant women who had taken Contergan often gave birth to children with severe malformations.
And yet, for several decades, medicine has placed great hope in the active ingredient again. Studies have shown, among other things, that it inhibits the growth of blood vessels, and thus may be suitable for cutting off tumors from their nutrient supply. Later, it also proved to be very effective for the treatment of multiple myeloma, malignant tumors in the bone marrow.
"We now know that thalidomide is a so-called molecular glue," explains Dr. Xinlai Cheng from the Institute of Pharmaceutical Chemistry at the University of Frankfurt. "This means that the active ingredient has the ability to grab two proteins and bring them close to each other." This is particularly interesting because one of these proteins is a kind of labeling machine: it attaches a label to the other protein that says, in large letters, 'must be disposed of'.
This label is recognized by the cellular garbage disposal system: it grabs the marked protein molecule and shreds it. "It is precisely this mechanism that explains the various effects of thalidomide," says Cheng. "Depending on which protein is labeled, this can lead to malformations during embryonic development or even kill a tumor."
For medicine, this mechanism opens up great possibilities. Cancer cells rely on certain proteins to survive. If these could be specifically destroyed, the diseases might be curable. The only problem is that molecular glue is quite specific. One of its binding partners is always the cellular labeling machine, technically: an E3 ligase called CRBN. Only very few of the many thousands of proteins in the body are suitable as the other partner – which ones exactly varies from glue to glue.
"We therefore produced a series of thalidomide derivatives," says Cheng. "Then we checked whether they have glue properties and, if so, which proteins they act against." To do this, the researchers added their derivatives to all proteins in a cell culture line. Afterwards, they checked which of these proteins were degraded in the presence of CRBN.
"We have encountered three derivatives that can mark a very important cell protein for degradation, BCL-2," explains Cheng. "BCL-2 prevents the suicide program of cells from being activated." If it is missing, the cells therefore perish." BCL-2 has therefore been the focus of cancer research for some time. There is even already a leukemia drug called Venetoclax, which prevents BCL-2 efficacy and thus drives degenerate cells to suicide.
The researchers tested their substances in fruit flies with tumor cells. The treated flies survived significantly better as a result. Although these results are still basic research, Cheng warns against excessive expectations: "They do show that modified thalidomide molecules have great therapeutic potential." However, it cannot yet be said whether the active ingredients will actually prove effective in practice at some point."
The work was supported by the DFG, Frankfurt Cancer Institute, and the PROXIDRUGS project.
