Molecular mechanisms of Ruthenium-based antitumor agents

In the last few years, two ruthenium anticancer 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 cisplatin and other related drugs are ineffective. The ruthenium drugs also show remarkably low toxicity which contrasts with other metal-based drugs. The biomolecular interactions of most metal-based drugs, from intravenous application to delivery to the cell and entry into specific organelles such as the nucleus, are largely unknown. This project aims to clarify the ambiguity surrounding these compounds by mapping the protein-drug interactions that occur in- and outside the cell for leading ruthenium metallodrugs. These 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). While it is known that DNA is not the main target of ruthenium-based drugs, the protein/enzymatic targets have not been identified. Without a knowledge of the drug target(s), rational drug design is problematic. Consequently, the aim of this project is to identify protein targets of ruthenium-based drugs within the cell, and also in serum. 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 due to its expertise in top-down and bottom-up proteomic strategies in metallodrug research, the Austrian partner will clarify the role serum proteins play in terms of enhanced transporter mediated cell uptake utilizing capillary electrophoresis (CE) and inductively coupled plasma-mass spectrometry (ICP-MS) techniques pioneered at this institution. In addition to the identification of the protein targets, a knowledge of the interactions of the drugs with the proteins on a molecular level will be established. Moreover, as the field of metal-based drugs is historically rooted in genotoxic agents that interfere with DNA, this project should lead to a new direction in the field of medicinal inorganic chemistry as the validation of proteins as targets will enable rational metallodrug design of enzyme targeted chemotherapeutics.