Project

Metal-protein interactions; Drug delivery; Molecular modelling; Proteomics

Lead
Lay summary
In this project we are studying a very promising new type of anticancer drugs that show selective toxicity in secondary (metastatic) cancers. Effective drugs for these secondary cancers are very limited and with surgical removal of primary cancers being well developed it is these secondary cancers are largely responsible for death in cancer patients. These new drugs developed at the EPFL termed RAPTA compounds are based on ruthenium and show remarkably low toxicity, like other ruthenium based compounds that are currently undergoing clinical trials. The exact mechanism by which these promising ruthenium antitumor compounds work remains unknown and in this project we intend to study their mode of action using chemical, biochemical, biophysical and theoretical methods. We intend to delineate the relevant targets and study in detail the binding mechanisms of the RAPTA compounds to them. A successful outcome of this project will be a greater understanding of the mechanism of action of the RAPTA drugs at a molecular level that should ultimately allow us to develop compounds that are superior to those currently available.

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Last update: 21.02.2013

Active participation

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Number	Title	Start	Funding scheme

Metastasis is the most deadly feature of cancer, accounting for greater than 90% of cancer-related mortality due to a lack of effective drugs. A few years ago we discovered a series of remarkably promising organo-ruthenium compounds that display selective activity against highly aggressive and metastatic tumors while apparently sparing healthy tissues. Based on the most recent studies (obtained in the last three years of this on-going project, and involving a number of vital national and international collaborations) we describe further relevant studies aimed at understanding the mode of action of these compounds in greater detail and in developing putative new derivatives with superior or targeted properties - notably a drug that we hope will show potential against invasive breast cancers. This current proposal builds on an existing and fruitful collaboration between the research groups of Paul Dyson (experimental approaches) and Ursula Röthlisberger (computational modelling) at the EPFL. Part of the research will be facilitated by key collaborations.The proposal is divided into three main sections with overlap and iterative processes connecting the various parts. Part 1 focuses on the critical role of transferrin as a carrier protein for site-specific drug delivery. Since serum transferrin (a protein that delivers iron to cells - cancer cells have a high requirement for iron with up to 10 times more transferrin receptors on their surface) is only about 30% saturated with iron, it has the capacity for binding to other metal ions that enter the body. Data show that RAPTA compounds have a lower efficacy in the absence of transferrin. Consequently, we intend to study the binding of RAPTA compounds to transferrin using a variety of biophysical tools and computational methods. The second part of the project extends on a recent crystallographic and bioanalytical study on the binding of a RAPTA compound to a nucleosome core particle. This study revealed that RAPTA-C binds exclusively to several sites of the histone protein core and not the DNA. In the next phase of this study we propose methods that should help us to learn how to modulate the site specificity of binding via control of steric and hydrophobic effects on the ring-substituents of the RAPTA structure. We also propose experiments that should help to unravel the connection between binding to the nucleosome (which appears to be highly relevant when compared to related data on cisplatin) and the pharmacological effects of RAPTA compounds. A detailed computational analysis of the obtained results is required to fully understand the binding preferences of RAPTA compounds. Additional experiments described in this part concerned with target identification are also planned.In the final part of the research program we describe the synthesis of new RAPTA compounds derivatized with doxorubicin, the latter being a front-line therapy for breast cancer, but marred by severe damage to healthy breast tissue. Combinations of doxorubicin and RAPTA-T were evaluated against both highly and poorly invasive human breast cancer cells, in comparison with non-tumoral human breast cells and it was found that RAPTA-T potentiated the doxorubicin-dependent inhibition of both protein and RNA synthesis, but not the DNA-damaging effects of doxorubicin and allowed doxorubicin to be applied in much lower doses with higher selectivity. Based on these data we have designed new RAPTA-doxorubicin hybrids and a series of relevant studies to evaluate the potential of these new compounds will be undertaken. Combined, it is hoped that these studies could lead to new therapies to treat tumors that have high mortality rates.