A new candidate for cancer drugs
Defeated a tumor in a test tube
A molecule has been found – a promising candidate for the role of
possible targeted anti-cancer drugLarisa Aksenova, <url>
However, the effectiveness of this molecule has so far been demonstrated only in a test tube.
An international group of scientists from the USA, France and China managed to suppress the activity of a mutant enzyme whose malfunction leads to leukemia. The painstaking work, which required monitoring of the library of candidate molecules, enzyme analysis and testing on cells of the TF-1 leukemic line, was crowned with success. A molecule with the classification number AGI-6780 has been named as a promising candidate for the role of a possible targeted (that is, directed against well-marked molecular targets) anticancer drug.
Many malignant tumor processes develop in the human body gradually and can begin with completely insignificant at first glance errors in the DNA sequence.
The replacement of just one nucleotide in the genes that encode enzymes with the complex name isocitrate dehydrogenase-1 and -2 (IDH1, IDH2) entails a cascade of changes leading to dramatic consequences.
The fact is that as a result of these mutations, the most important part of the enzyme, its active center, where the catalysis of biochemical reactions takes place, begins to work incorrectly. As a result, instead of providing a key process of cell metabolism – the reaction of converting citric acid into alpha-ketoglutaric acid – the enzyme begins to produce huge amounts of 2-hydroxyglutarate. In recent years, scientists have had enough reasons to call this substance oncometabolite.
Various forms of glioma, secondary glioblastomas, chondrosarcoma, cholangiocarcinoma, acute myeloid leukemia – this is an incomplete list of oncological diseases accompanied by a noticeable increase in the concentration of 2-hydroxyglutarate. In some cases, for example, with glioma, its concentration in cells can increase a hundred times.
In 2009, researchers from Agios Pharmaceuticals (Cambridge, USA) were able to prove that the mutated isocitrate dehydrogenase (mentioned above) begins to produce 2-hydroxyglutarate instead of alpha-ketoglutarate. This work was very important because it explained where such an excessive amount of 2-hydroxyglutarate comes from in an organism in which an irreversible cancer process is "gaining momentum" in many cases. The results of the study were published in the journal Nature. At the same time, the question arose: is it possible to silence a mutant enzyme? The scientists of Agios Pharmaceuticals directed all their efforts to search for molecules that could cope with such a task. In their search, they teamed up with biologists from France and China.
And now a possible contender has been found. In an article published in Science (Wang et al., Targeted Inhibition of Mutant IDH2 in Leukemia Cells Induces Cellular Differentiation), researchers report that a small molecule (from a chemical point of view, a heterocyclic sulfonamide derivative), which was named AGI-6780, is capable of powerfully and selectively inhibiting the biochemical manifestation of the IDH2/R140Q mutation, associated with the development of a tumor. However, so far with one caveat – in a test tube.
The substance was introduced into a nutrient medium in which cells of the TF-1 leukemic line grew. As a result, undifferentiated cancer cells began to show signs of specialization, changing shape and size, and the synthesis of 2-hydroxyglutarate in them decreased tenfold – depending on the concentration of AGI-6780.
It was also possible to find out exactly how this substance interacts with the enzyme: it binds to two IDH2 subunits at once at the place of their "contact" and causes conformational ("architectural") changes. This leads to a noticeable decrease in the activity of the "defective" enzyme. Scientists hope that the AGI-6780 molecule, which purposefully suppresses the work of IDH2, has a chance in the future to become one of the most important drugs in the arsenal of targeted (targeted) cancer therapy. It should be noted that in real life, the IDH2/R140Q mutation occurs in 9% of patients with acute myeloid leukemia.
At the same time, statistics show that few candidate molecules become full-fledged medicines in the future. A long period of verification of the candidate molecule - usually at least 10 years – not only in laboratory experiments, but also in preclinical and clinical trials should confirm that the molecule is safe and effective in real "combat" conditions on the guard of human health.
Portal "Eternal youth" http://vechnayamolodost.ru15.04.2013