Design of metal-based dual-activation ALK-inhibitor prodrugs

Every fourth inhabitant of Austria will develop cancer in the course of his/her life. These diseases lead both to severe limitations in the quality of life of patients and to an enormous burden on the Austrian health care system. Cancer is a collective term for many different diseases, all of which are based on genetic changes in cells. These changes allow those cells to acquire properties that healthy cells do not have - such as unhindered cell growth (tumor formation), the ability to invade surrounding tissue ("invasiveness") and the formation of satellite tumors in distant tissue (metastasis). The development of these properties is based, among others, on the increased production of a certain type of enzymes called tyrosine kinases. Since the beginning of the new millennium, these enzymes have served as points of attack for modern chemotherapy using small, synthetic molecules (e.g., tyrosine kinase inhibitors) or monoclonal antibodies the so-called targeted therapeutics. However, since these enzymes are also found in healthy body cells, treatment with these active ingredients sometimes has severe adverse effects that can even lead to the discontinuation of therapy. In addition, due to the strong side effects, it is rarely possible to apply several tyrosine kinase inhibitors simultaneously and in high doses. One way to reduce side effects is to use a so-called prodrug concept, in which an active ingredient is modified with a chemically activatable masking unit. This unit should be stable in healthy cells, suppress the biological effectiveness of the active substance and only be activated in tumor cells. Due to their altered biological properties, tumor cells also have characteristics that healthy body cells do not have which can be exploited to release the active ingredients (e.g., different pH values or dead cell areas inside a tumor). However, the development of such "masking units" is complex and mostly based on a "trial and error" principle. As a result, large substance libraries have to be built up in a time- consuming manner, which causes high costs and consumes a large amount of resources. Therefore, during this project, a computer-aided process will be developed to first model these "masking units" and then to compare their calculated properties. From a large number of these model substances, the most promising candidates will be synthesized, their biochemical and biological properties examined and compared with the calculated ones. As a result, the synthetic effort can be minimized and a process can be developed to directly conclude important properties for the activation of the prodrugs based on their chemical structure. The major difference to common state-of-the-art approaches is the intensive integration of computer- aided methods in rational prodrug development. The goal is the development of potential chemotherapeutic agents that have fewer side effects than the tyrosine kinase inhibitors that have been clinically approved to date.