Lead


Lay summary
Although deaths caused by communicable diseases are predicted to decline in the course of the next 25 years, mortality due to non-communicable diseases, such as cancer, are expected to rise. This prognosis is based on the ageing global population, and while certain cancer-promoting lifestyle choices are becoming less common, e.g. smoking, it is predicted that by the year 2030, non-communicable conditions will account for approximately 70% of all deaths worldwide with malignancies being the single largest contributing factor.In the last few years, two ruthenium drugs have entered clinic trials generating considerable interest in the medicinal properties of ruthenium compounds. These drugs are effective against primary tumours and metastasis, for which standard treatment options are ineffective. The ruthenium drugs also show remarkably low toxicity which contrasts with other metal-based drugs.Within the project, we will characterize the biomolecular interactions of these promising, next-generation metallodrugs, as the reactions taking place from intravenous application to delivery to the cell and entry into specific organelles such as the nucleus, are largely unknown. The project aims to clarify the ambiguity surrounding these compounds by mapping the protein-drug interactions that occur in- and outside the cell. The compounds will consist of KP1019/1339 and NAMI-A (the two ruthenium drugs currently under clinical investigation) as well as RAPTA-T (a highly promising ruthenium(II)-arene anticancer compound which shows selectivity in metastatic cancers).Without a knowledge of the drug target(s), rational drug design is problematic. Consequently, the aim of this project is to identify targets of ruthenium-based drugs within the cell, and also in blood (important for the evaluation of side-effects). In order to achieve these highly challenging tasks, the project will be carried out in collaboration between the EPFL and the University of Vienna. The Swiss partner will focus on the interactions on the cellular level, while the Austrian partner will clarify the role serum proteins play, especially in terms of enhanced transporter-mediated cell uptake.This project should lead to a new direction in the field of medicinal inorganic chemistry: up to now, only DNA was considered as a possible target for metal-based drugs, but we intend to confirm proteins and enzymes as more interesting and specific targets. Ideally, our results will enable rational metallodrug design for enzyme targeted chemotherapeutics, which will increase the treatment options for currently incurable cancers with minimal impact on the patients' quality of life by reducing side-effects.