Design and synthesis of dimethylisoxazole quinolines as BET inhibitors

Rights statement
Awarding institution
  • University of Strathclyde.
Date of award
  • 2015
Thesis identifier
  • T15984
Qualification Level
Qualification Name
Department, School or Faculty
  • Gene regulation is governed by the assembly of protein complexes capable of reading post-translational modifications (PTMs) on chromatin. Bromodomains read acetyl-lysine PTMs on histone tails and are important determinants of epigenetic memory. Dysregulation of epigenetic processes has been shown to contribute to human disease and inhibitors of bromodomains, in particular, represent an emerging class of potential treatments and investigational tools. This thesis describes the research completed towards the design and synthesis of inhibitors of Bromodomain Extraterminal (BET) proteins, a family of bromodomain-containing proteins characterised by their tandem bromodomain modules. In the first section, compounds from a series of dimethylisoxazole quinoline BET inhibitors were investigated for their potential as intravenous-administered drug pre-candidates. A detailed account of improving compound solubility and efforts to overcome a human ether-a-go-go related gene (hERG) developability issue is provided. Building on results gathered in the early stage of this research, a pyridine ring was used to lower lipophilicity compared to a phenyl ring and, in the case of an N-methylpiperazine substituted aryl ring, this transformation successfully abolished hERG activity. These encouraging data, combined with those obtained from biochemical, phenotypic and aqueous solubility assays, established the N-methylpiperazine substituted pyridine as the lead compound within this programme of research at that point in time. The second section details the development of a small molecule probe selective for the first bromodomains (BD1s) of the BET proteins. Here, a programme of research to enhance the selectivity and potency of the dimethylisoxazole quinoline series of inhibitors towards the BD1 domains is described. Using both data-driven and structure-based design, a dimethylisoxazole imidazolquinoline was developed and, upon screening, was found to exceed the programme requirements regarding potency and domain-selectivity. This molecule was used as a probe in biological studies alongside pan-BET inhibitors and demonstrated that the anti-inflammatory and antiproliferative phenotype typical of pan-BET inhibition was retained upon selective BD1-inhibition. With increasing interest in scientific community for the development of domain-selective BET inhibitors and their use in biological experiments, these studies provide an important foundation for further research in this specific arena.
Advisor / supervisor
  • Kerr, William
  • Watson, Robert
Resource Type
  • Previously held under moratorium in Chemistry department (GSK) from 1/6/15 until 3 September 2021.
  • The confidentiality statement on each page of this thesis DOES NOT apply