Kinases versus cancer

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FACULTY OF BIOCHEMISTRY, BIOPHYSICS AND BIOTECHNOLOGY

 

Modern anti-cancer therapies utilize a series of drugs whose activity consists of binding to target proteins called kinases. The objective of the research conducted at the Faculty of Biochemistry, Biophysics and Biotechnology and at the Malopolska Centre of Biotechnology, both at the Jagiellonian University, is to determine, on the atomic level, the structure of kinases relevant in cancer. Such information constitutes indispensable support for the process of structure-based drug design.

Kinases are enzymes that are responsible for information transmission within living cells. They also participate in various metabolic processes. Many kinases act as specific molecular "switches" allowing the activation of various proteins in response to various external and internal stimuli. Kinases create a complex network of interdependencies, so-called signal transduction pathways. The activity of such networks is based on reversible activation of kinase action that in turn regulates the activity of other proteins. In this specific manner kinases regulate gene expression and the activity of a number of proteins, depending on current physiological needs. This allows optimal use of available resources as well as proper cell development and growth.

In cancer cells, some of the kinases exhibit excessive activity, which, as a consequence, contributes to uncontrolled tumor growth and its spreading throughout the body. It has been observed that in numerous types of cancer the inhibition of the activity of selected kinases provides therapeutic benefit, which makes the inhibitors of these enzymes an interesting subject of research in modern biotechnology.

Kinase inhibitors cure cancer

One of the modern ways to treat cancer employs special inhibitors – molecules that block kinase activity. The success of the first marketed kinase inhibitors led to dynamic development of studies on these compounds, which makes it possible to expect further improvement of treatment efficiency. Understanding the structure of kinases at the atomic level facilitates the design of highly specific and effective inhibitors. It also makes it possible to describe the molecular mechanisms of action for already known drugs.

The aim of the research carried out by scientists from the Jagiellonian University is both to determine the structure of kinases with currently known inhibitors as well as to solve atomic structures of those kinases whose structures remain unknown. This will in turn enable the computer aided design of molecules that will fit perfectly into the active site and – after binding to it – will block the excessive activity of the given kinase and thus will actively stop or limit the uncontrolled growth of cancer cells. This method, which has been used successfully in drug discovery, is called structure-based drug design.


Kinase structure with the inhibitor marked in green

 

Insight into the protein crystal

In order to solve the structure of proteins, X-ray crystallography is used. It is a method that employs X-rays to describe the structure of molecules building the crystalline lattice. The extreme power of X-ray crystallography as a research tool is proven by the fact that, since the beginning of the 20th century, 26 Nobel Prizes have been awarded for research connected with crystallography, of which one of the most important ones was the prize awarded for the discovery of the structure of DNA by Watson, Crick and Wilkins.

Macromolecules such as proteins and nucleic acids, when placed in a suitable chemical environment, form crystals several tens of micrometers in size. What is characteristic for such crystals is the fact that they are composed of a huge number of symmetrically arranged protein molecules, which are organized in the form of a dense, regular network. Such an ordered structure of the crystal allows the high-energy X-ray beam to diffract, so that scientists are able to calculate the exact position of individual atoms within the protein based on the way the beam diffracts on the crystal.

In everyday research work relatively weak laboratory sources of X-rays are used. However, the enormous possibilities of modern crystallography can be discovered only when using synchrotron sources, e.g., the "Solaris" synchrotron, which is currently under construction on the Third Campus of the Jagiellonian University. Synchrotrons are highly complex and expensive research installations used in protein crystallography, but also in numerous other fields, such as physics or material science. A highly simplified definition of a synchrotron is a long, closed tunnel in which electrons accelerated to a velocity close to the speed of light are circulating in an ultra-high vacuum. In these conditions radiation is generated, including X-ray radiation, which in protein crystallography is directed at a protein crystal. Dedicated, sensitive detectors gather information about the diffracted X-rays, which are then processed by a computer generating the structure of a protein. As adequate sources of synchrotron radiation are still not available in Poland, to this point sources located in other European countries have been used for the purpose of research on protein structure conducted by scientists from the Jagiellonian University. The completion of the construction of the National Synchrotron Radiation Centre "Solaris" will enable the crystallographers from the Jagiellonian University to study the structures of kinases and of other proteins even more efficiently.

Structural studies of kinases that play an important role in cancer are a new undertaking at the Jagiellonian University. The first tangible success of the project was participation in studies explaining the role of glucokinase in abnormally multiplying white blood cells. The research is continued in co-operation with scientists from the German Cancer Research Center in Heidelberg (Germany) and from the St. Jude Children's Research Hospital in Memphis (USA). Its objectives include the characterization of the molecular structure of this protein, which may in the future facilitate the development of modern drugs for diseases such as leukemia.


Research team: Grzegorz Dubin, PhD; Przemysław Grudnik, PhD; Krzysztof Rembacz, PhD; Małgorzata Romanowska, PhD; Józefina Bogusz, MSc; Karol Źrubek, MSc