Bullets against cancer
"Five liters of red: What you need to know about blood, its diseases and treatment"
Blood supplies us with oxygen, delivers nutrients to the tissues of the body and performs other important functions. If something goes wrong with the blood, the consequences can be serious. At the same time, it is quite difficult to diagnose hematological diseases. In the book "Five liters of red: What you need to know about blood, its diseases and treatment" (Alpina Publisher), hematologist-oncologist Mikhail Fominykh talks about the anatomy and physiology of blood and hematopoietic organs, benign and malignant blood diseases, as well as modern methods of their diagnosis and treatment. We publish a fragment dedicated to the history of the creation and mechanism of action of protein kinase inhibitors.
Bullets against Cancer — protein kinase inhibitors
As of September 2020, the FDA, the main regulatory authority for drug trafficking in the United States, has approved about 75 different protein kinase inhibitors for the treatment of a huge number of diseases. An impressive achievement, considering that the first drug of this class, imatinib, was approved for the treatment of CML in 2001. And every year their number continues to increase.
Protein kinase inhibitors today are one of the types of targeted therapy, in which they deliver a targeted blow to the target. The target for the drug in this case is a specific molecule in the body, whose biochemical function is closely related to the occurrence and (or) development of a certain pathology, the effect on which the drug molecule gives a therapeutic effect. In May 2001, Time magazine put a scattering of imatinib pills (trademark Glivec) on the cover and dubbed them bullets in the fight against cancer.
The era of this group of drugs began with the creation of imatinib, it was he who became the ancestor of targeted therapy.
The story of imatinib will begin from afar. As I mentioned earlier, according to the Denver Classification, each pair of chromosomes has a number assigned to it. The 9th and 22nd chromosomes take part in the formation of a cytogenetic anomaly, the so-called Philadelphia chromosome. On the 9th chromosome there is a section called ABL (Abelson), and on the 22nd - BCR (breakpoint cluster region). As a result of the failure, there is a mutual exchange of chromosome sections (translocation) and an altered 9th and Philadelphia chromosomes are obtained.
When the BCR and ABL regions are located next to each other on the Philadelphia chromosome, a mutant hybrid gene BCR-ABL1 is formed, encoding the synthesis of the oncogenic protein BCR-ABL. This gene turns normal cells into malignant cells. How does this happen? From a section of the ABL gene, the protein receives the abilities of tyrosine kinase, an enzyme involved in the transmission of signals that prompt the cell to divide, and the part encoded by the BCR gene contributes to its activation. Such a tyrosine kinase with increased activity stimulates cell division without regard to the usual regulatory mechanisms. As a result, the cells begin to grow and divide uncontrollably, which leads to the formation of a huge number of white blood cells in the body. Excessive activity of kinase enzymes underlies many oncological diseases, and CML in particular.
The fact that the trigger mechanism for the development of CML is the activation of BCR-ABL-tyrosine kinase became known by the mid-1980s. However, this was only part of the case. It was necessary to find a chemical compound that effectively affects the found target and is able to stop the pathological process. The beginning of the search, oddly enough, dates back to 1977, when Japanese microbiologists isolated the antibiotic staurosporin from a culture of soil bacteria Streptomyces staurosporeus. In 1986, it was shown that staurosporin is an inhibitor of protein kinases (a subclass of kinase enzymes) of low selectivity. This caused an explosion of interest on the part of pharmaceutical companies in the search for such inhibitors by screening natural compounds and libraries of chemicals; in particular, researchers from the Swiss company Ciba-Geigy (later, in 1996, through the merger of Ciba-Geigy and Sandoz formed the pharmaceutical giant Novartis) found that derivatives of 2-phenylaminopyrimidine have a narrow specificity by binding only one kinase. In 1992, Ciba-Geigy chemist Jurg Zimmermann (born 1957) synthesized the compound CGP 57148B (imatinib mesylate), which was an inhibitor of BCR-ABL tyrosine kinase.
In 1993, American oncologist Brian Drucker (born 1955) conducted a series of experiments during which he added CGP 57148B to CML cell colonies. Experiments invariably ended with the fact that leukemic cells, unlike healthy ones, died overnight. This was followed by experiments on mice, and clinical trials on patients began only in 1998.
In 2001, imatinib was approved by the FDA for use under an accelerated program, as it demonstrated amazing results in treatment. The vast majority of patients manage to achieve stable and complete remission. With the advent of imatinib, it was possible to turn a deadly disease into a controlled chronic disease. Patients continue to lead a normal lifestyle, do their usual things, continue to work, build families and give birth to healthy children, and since 2010, clinical studies have been conducted to cancel therapy in some patients (before that, it was believed that therapy should be lifelong).
I have dwelt on the description of imatinib in such detail only because it was the ancestor of a new class of drugs — tyrosine kinase inhibitors. He still did not become a miracle wand. The main problem that arises when using imatinib for the treatment of CML is the resistance to it that develops over time, associated, in particular, with various mutations of the BCR-ABL1 gene encoding hyperactive tyrosine kinase: more than 100 mutant forms of BCR-ABL tyrosine kinase have already been described. Over the past two decades, extensive experience has been accumulated in the treatment of CML and new drugs have appeared for the treatment of imatinib-resistant patients. The drugs of the next generation (nilotinib, ponatinib) are superior in effectiveness to imatinib, but they are also much more expensive, which greatly limits their widespread use.
Of course, tyrosine kinase inhibitors are aimed not only at BCR-ABL tyrosine kinase, in clinical practice, for example, Bruton tyrosine kinase inhibitors are used for the treatment of chronic lymphocytic leukemia. To date, a large number of "targets" for exposure to drugs are being studied. And we have seen how in recent years new targeted drugs have been confidently entering clinical practice, and, most likely, this is just the beginning. Due to the constant improvement of understanding of the role of individual molecules and signaling pathways in the pathogenesis of various diseases in the future, we can expect the creation and introduction to the market of more and more such drugs, which, due to increased specificity, will obviously also be more effective and safe.
The drugs discussed in this chapter belong to the so-called small molecules. Their synthesis is carried out in the classical way: through chemical reactions between various organic or inorganic compounds. The line separating them from drugs that have long been in practice is quite conditional — the human body is an incredibly complex biochemical system, so that the high selectivity of targeted drugs can only be called with many reservations — taking the same tyrosine kinase inhibitors is sometimes accompanied by dermatological side effects.
In a sense, here the word "targeted" is more appropriate to apply to the process of searching for such drugs. We know the "target" and are looking for a low-molecular-weight drug aimed against it. Such directed design of new drugs has been called "drag design". Virtual screening of huge libraries of compounds allows you to select various variants of structures with potential activity in relation to the target protein, and modern automated methods of combinatorial chemistry give researchers the opportunity to synthesize a huge number of compounds and carry out the selection process (screening) of the most active.
But it turns out that you can entrust the process of finding medicines to nature, which has accumulated a lot of experience in this matter. However, it works somewhat cliched, preferring to design large molecules. And in the next chapter we will talk about them.
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