Russian candidate for Blood cancer drugs
Fighting leukemia at the molecular level
The drug is a tyrosine kinase inhibitor.
If you recall the basics of biology, you can guess that this drug stops or slows down (as an inhibitor should) the activity of some protein enzyme - tyrosine kinase. To understand why this is necessary and what tyrosine kinase does in a cell, it is necessary to get acquainted with an important concept of molecular biology – phosphorylation.
Phosphorylation is an epoch–making process that happens in the life of every protein. It is after phosphorylation that the protein begins to perform its work in the cell. This process consists in the fact that the PO 4 group is split off from the ATP molecule and attached to the protein molecule. After that, the protein is activated.
This operation is performed by special proteins called kinases. Depending on which amino acid the kinase attaches the phosphate group to, there are different types of kinases. If the attachment occurs to tyrosine, then tyrosine kinase does it.
The processes of the cell life cycle: cell growth, cell differentiation, division and death depend on the proteins that tyrosine kinase phosphorylates. As a rule, substances regulating these processes ("growth factors") come from outside, enter the cell membrane and there meet with a receptor containing tyrosine kinase. The receptor is activated, tyrosine kinase begins to phosphorylate certain proteins, the cell begins to grow or divide.
So everything happens normally: kinases rule the life of the cell, starting the necessary processes in time. But if the course of their work is disrupted, the consequences will be sad. Excessive kinase activity underlies many oncological diseases, because this activity leads to uncontrolled cell growth and division.
Actually, scientists discovered the first tyrosine kinase in 1980, studying the oncological disease of chickens – Raus sarcoma. This disease is transmitted by a virus. In the course of evolution, this virus "picked up" a gene encoding tyrosine kinase from some other organism. During its lifetime in the viral genome, this gene has been modified somewhat, and now, when the virus enters the chicken cell, tyrosine kinase begins to work hard and eventually causes Raus sarcoma.
Chronic myeloblastic leukemia is also associated with tyrosine kinase activity. This disease in the vast majority of cases occurs as a result of a mutation, which was called the "Philadelphia chromosome", Peter Nowell worked in Philadelphia (University of Pennsylvania) and David Hungerford (Fox Chase Cancer Center), who discovered this mutation in 1960. The "Philadelphia chromosome" occurs as a result of the exchange of sites between the ninth and twenty-fifth chromosomes. After that, one protein is synthesized in the body instead of two. It was named BCR-ABL. It causes unrestrained activity of tyrosine kinase, which phosphorylates without rest, which is perceived by the cell as a signal for growth and division. Eventually, myeloblastic leukemia develops. The Philadelphia chromosome is responsible for 95% of cases of chronic myeloblastic leukemia and a certain number of cases of acute.
Of course, scientists, having understood the mechanism of the disease, aimed at developing a means to stop the pathological activity of tyrosine kinase, that is, for the creation of an inhibitor. In the late 1990s, the first highly effective drug was created - imatinib. It is also known by the commercial name "Glivek". The use of the new drug was authorized in the United States in May 2001, after two years of clinical trials, it was developed by a group of scientists led by Nicholas Lydon, Charles Sawyers and Brian Drucker. We have already talked about their work, listing potential candidates for the Nobel Prize in Physiology or Medicine.
"Glivek" does not rid the patient of myeloblastic leukemia permanently, but allows him to live by regularly taking medication, just as diabetic patients take insulin. The inhibitor, entering the body, suppresses the deadly activity of tyrosine kinase, and myeloid leukemia does not develop.
The creation of Glivek was a big breakthrough in the fight against leukemia, the like of which had never been before. Time magazine put an image of the drug on the cover, calling it a "bullet" against cancer. In 2009, Drucker, Lydon and Sawyers received the Lasker-DeBakey Clinical Medical Research Award for their success in "turning deadly cancer into a controlled chronic disease." Soon followed the creation of a number of similar drugs: dasatinib ("Sprycel"), nilotinib ("Tasigna"), ponatinib ("Iclusig") and others.
Pharmaceutical companies around the world continue to search for new drugs. Why is this necessary if there is a "Givek"? The fact is that there are a number of mutations in the Philadelphia chromosome that make tyrosine kinase resistant to the action of Glivec. Therefore, new drugs are required for these forms of leukemia.
Also, Glivek and other existing tyrosine kinase inhibitors are not without other drawbacks. They can cause side effects of varying severity. Finally, they are just very expensive. If the average working Russian is most often able to pay for regular insulin intake (the average pensioner is not always, but often), then unfortunately, there can be no question that the average Russian, or even an American, can pay for his "Glivek". Recall that in 2013, more than a hundred oncologists, including the creator of Glivek, Brian Drucker, published an open letter in the scientific journal Blood, in which they called the immoral price demanded for the drug by the manufacturer, Novartis. In 2001, the cost of the annual imatinib course was $ 30,000, but by 2012 it had increased to 92,000, which brings the manufacturer 4.2 billion dollars a year. Scientists claim that the costs of developing and clinical trials of the drug were covered by the first billion dollars raised by the company, all the rest is net profit.
Here, of course, it can be argued that the profit from Novartis Glivec pays not only for its creation, but also for many developments that did not bring results, as well as future research and the creation of new drugs. But, no matter how to evaluate the actions of the manufacturer, we must admit that the high price makes Glivek and similar drugs inaccessible to many patients.
Therefore, the development does not stop. Fusion Pharma is also engaged in this. In the search for new drugs, modern methods of "rational drug design" are used, when research begins with computer modeling of the molecular structure of a potential drug. The program scans a huge number of substances, selecting from them those whose molecules meet the specified conditions. Only those few substances that are on the "shortlist" pass to the next stage, when the work is transferred from the computer to the laboratory and in vivo tests begin. After successful animal trials, it is possible to proceed to the clinical trial of a new drug in humans.
At the moment, the drug PF-114, which was developed at Fusion Pharma, has shown high efficiency in laboratory tests. He successfully copes with myeloid leukemia, including those forms of the disease that are resistant to other existing drugs: Glivec, Tasigne, Sprycel. Experiments also confirm the high selectivity of the action of PF-114, that is, the minimization of possible side effects. In the future, the developers plan to switch to international clinical trials of this drug.
In conclusion, it should be noted that protein kinase inhibitors, including tyrosine kinases, are promising not only in the fight against chronic myeloblastic leukemia. There are a number of other diseases caused by the pathological activity of various tyrosine kinases, (including non-small cell lung cancer, kidney cancer, glioblastoma, myelofibrosis, rheumatoid arthritis, retinal dystrophy) therefore, these diseases can also be dealt with by creating a suitable inhibitor.
Portal "Eternal youth" http://vechnayamolodost.ru25.04.2014