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Title: Unravelling the targets of electrophilic natural products in cancer with chemical proteomics
Author: Clulow, James
ISNI:       0000 0004 6348 1139
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2015
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Electrophilic natural products that are found in dietary sources such as curcumin, piperlongumine and sulforaphane have attracted considerable interest on account of their broad range of biological activities, leading to their assessment as therapeutics for a number of diseases. Despite extensive research, the mode of action and biological targets of these compounds remain poorly understood. These compounds are clearly not 'single target' molecules; dissecting their complex polypharmacology to determine the key targets and pathways presents a major challenge, and has limited progress in the clinic. In this study, a chemical proteomics approach using activity-based probes (ABPs) based on these small molecules has been applied to allow the profiling of their molecular targets in breast cancer cellular systems, identifying the range and relative importance of targets that these molecules bind to covalently, across the entire system in an unbiased way for the very first time. Hundreds of high confidence targets have been unravelled, providing the most comprehensive protein target set for curcumin, piperlongumine and sulforaphane to date. Translation of these targets to the mode(s) of action displayed by these compounds reveals new mediators that help to explain their anticancer effects. The previous limited target information has been a major hindrance in determining how best to apply such electrophilic natural products as therapeutics. These studies address this void and help to provide greater clarity into the underlying mechanisms of curcumin, piperlongumine and sulforaphane, as well as electrophilic natural products more generally.
Supervisor: Tate, Edward Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral