Development of mass spectrometric methods to understand the mechanism of action of transition metal-based anticancer compounds

Metal based anti-cancer drugs (metallodrugs) such as cisplatin are a cornerstone of cancer chemotherapy. However, development of this class of compound has been hindered by our lack of understanding of how they function. This is mainly because existing method to study the mechanism of action of metallodrugs are lacking as they were either directly adapted from methods to study organic drugs which have very different chemical properties or current limits in technology and knowledge were a bottleneck to the development of suitable methods. Mass spectrometry (MS) has emerged as a powerful tool which can be applied to study the mechanism of action of metallodrugs. Many different MS methods exist which can be adapted to study different aspects of drug action while accounting for the unique chemical nature of metallodrugs. In this dissertation, we develop MS strategies to study how platinum and ruthenium metallodrugs work and study a few important aspects of their function. Firstly, the in vitro distribution of and ligand state of metallodrugs were studied by imaging mass spectrometry. Next, we attempted to find novel protein targets of metallodrugs using a novel protein expression profiling approach. Promising metallodrug protein targets obtained from this study were then validated via biochemical methods. To facilitate the application of MS based protein-metallodrug fragmentation experiments for finding binding sites of metallodrugs on proteins, we developed and optimized web-based tools for automatic processing of complex spectra from these experiment. We then applied these tools to study the interaction of metallodrugs on relevant proteins, which provided insight into the specific binding properties of metallodrugs on proteins.


Advisor(s):
Dyson, Paul Joseph
Johnsson, Kai
Year:
2016
Publisher:
Lausanne, EPFL
Keywords:
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis7234-7
Laboratories:




 Record created 2016-10-31, last modified 2019-05-09

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