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Title: Chemical probes for histone lysine demethylases
Author: Gerken, Philip
ISNI:       0000 0004 6494 2216
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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The primary objective of this DPhil research project was to develop selective and cell-active inhibitors of the histone lysine demethylase KDM2A, which could potentially lead to the discovery of a novel chemical probe. Chapter one of this thesis introduces the role of histone lysine demethylases (KDMs) in the epigenetic regulation of gene expression and discusses the value of chemical probes as tools to study these enzymes. Chapter two describes the synthesis of a library of indoline-based KDM2A inhibitors using a modular synthetic approach to explore key structure-activity relationships and a chiral counterion-mediated strategy to synthesize lead candidates enantioselectively. Chapter three discusses investigations into the cellular activity of lead compounds and explores strategies to address limitations associated with cytotoxicity and promiscuity. Chapter four describes the application of a variety of experimental techniques to identify the mode of target inhibition. Finally, chapter five focuses on the development of an enantioselective C-acylation reaction to access spirocyclic fragments asymmetrically.
Supervisor: Smith, Martin Derwyn ; Brennan, Paul Sponsor: Systems Approaches to Biomedical Sciences Centre for Doctoral Training
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Chemistry ; Chemical Probes ; Epigenetics ; Lysine Demethylases