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An Integrated Approach to Study the Molecular Mechanisms of Ruthenium-Based Antitumour Agents (D-A-CH/LAV)

English title An Integrated Approach to Study the Molecular Mechanisms of Ruthenium-Based Antitumour Agents (D-A-CH/LAV)
Applicant Dyson Paul
Number 130647
Funding scheme Project funding (special)
Research institution Laboratoire de chimie organométallique et médicinale EPFL - SB - ISIC - LCOM
Institution of higher education EPF Lausanne - EPFL
Main discipline Inorganic Chemistry
Start/End 01.01.2011 - 31.12.2012
Approved amount 133'519.39
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All Disciplines (2)

Discipline
Inorganic Chemistry
Biochemistry

Keywords (10)

metal-based drugs; protein binding; proteomics; mode of action; ruthenium; biological targets; drug discovery; medicinal chemistry; bio-analytical chemistry; target identification

Lay Summary (English)

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.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Anthracene-Tethered Ruthenium(II) Arene Complexes as Tools To Visualize the Cellular Localization of Putative Organometallic Anticancer Compounds
Nazarov AA, Risse J, Ang WH, Schmitt F, Zava O, Ruggi A, Groessl M, Scopelitti R, Juillerat-Jeanneret L, Hartinger CG, Dyson PJ (2012), Anthracene-Tethered Ruthenium(II) Arene Complexes as Tools To Visualize the Cellular Localization of Putative Organometallic Anticancer Compounds, in INORGANIC CHEMISTRY, 51(6), 3633-3639.

Collaboration

Group / person Country
Types of collaboration
Universität Wien Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
125173 Rational design of organo-ruthenium anticancer compounds with novel modes of action 01.04.2009 Project funding
133788 Metallomic Studies Using Electrospray Ionisation-Mass Spectrometry (ESI-MS) 01.12.2010 R'EQUIP

Abstract

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 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.
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