Thesis
The design and synthesis of novel epigenetic modulators
- Creator
- Rights statement
- Awarding institution
- University of Strathclyde
- Date of award
- 2014
- Thesis identifier
- T15976
- Person Identifier (Local)
- 201060227
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- This thesis describes the design and synthesis of small molecule epigenetic inhibitors, motivatedby the identification of disease treatments which will provide innovative medicines for patients.The work reported is focused on the identification of compounds which bind to thebromodomains of the BET family of proteins. These bromodomains have been implicated in anumber of therapeutic areas, including oncology and immuno–inflammatory diseases.In Part I, an introduction to current challenges in drug discovery sets the scene for the workreported within this thesis. The science of epigenetics is introduced, and key medicinalchemistry themes relevant to these PhD studies are presented.In Part II, an orally bioavailable BET bromodomain inhibitor suitable for clinical progressionwas identified, the first such example from the dimethylisoxazole series of compounds.Medicinal chemistry was focused on SAR generation, and the control of physicochemicalproperties by the use of in silico profiling. Ultimately, the pre-clinical candidate molecule wassynthesised on a large scale to provide material for further in vivo safety and efficacy studies.In Part III, esterase sensitive motif (ESM) technology was used to target molecules to cells ofthe monocyte/macrophage lineage with the aim of improving tolerability. ESM technology wasincorporated into BET bromodomain inhibitors, and molecules were identified to probe theviability of this approach in the BET bromodomain area.In Chapter 3, preliminary work was undertaken to establish a successful proof of principle forthe use of ESM technology within the BET bromodomain area. In Chapter 4, the chemicalseries was further developed, resulting in an increased cellular potency of the molecules. As aresult, an in vitro probe molecule was identified which could be used to further elucidate BET–ESM technology.In Chapter 5, medicinal chemistry design was focused on improving the drug-like properties ofthe series, increasing cellular permeability, and reducing in vitro clearance. By balancing theseproperties, a molecule was identified for in vivo profiling, and is currently under investigation toassess its suitability as a pre-clinical candidate molecule.
- Advisor / supervisor
- Bit, Rino
- Suckling, C. J. (Colin J.)
- Resource Type
- Note
- Previously held under moratorium in Chemistry department (GSK) from 27 October 2014 until 18 June 2021
- The confidentiality statement on each page of this thesis DOES NOT apply
- DOI
- Funder
- Managing organisation
- Epinova Discovery Performance Unit, GlaxoSmithKline
Relazioni
Articoli
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