Increasing the saturation of BET inhibitors

  • Joseph Dixon

Student thesis: Doctoral Thesis


Bromodomains are epigenetic reader modules that are found as part of multidomain proteins. They recognise acetylated lysine residues on histone tails in order to regulate gene expression. Bromodomain and extra-terminal domain (BET) proteins are a family of bromodomain-containing proteins that consist of BRD2, BRD3, BRD4 and BRDT. Each of these contains the tandem bromodomain modules, BD1 and BD2. BET proteins are an interesting target for drug discovery that has emerged in recent years, with numerous pan-BET inhibitors being reported to have anti-inflammatory and anti-proliferative properties.A chemoinformatic analysis has demonstrated that, compared to approved drugs, reported BET inhibitors had relatively low three-dimensional character.1 In other words, they are highly unsaturated, flat molecules. The relevance of this is explained in the “Escape from Flatland” papers, wherein empirical analysis demonstrated that drug candidates with a higher degree of saturation are likely to be less promiscuous, more soluble and overall be more likely to succeed to market.2,3This research set out to develop a series of pan-BET inhibitors with an increased degree of saturation to those existing in the literature. The approach taken involved replacing a phenyl ring in a well-established inhibitor fragment with a saturated analogue, and exploring the vectors produced. During this process a molecule was discovered that had unexpected selectivity for the BD2 domain of BRD4 over the BD1 domain.There are very few published examples of BD2-selective BET inhibitors, and as a result there is limited understanding of how the biological roles of BD2 domains differ from their BD1 counterparts. Therefore, the direction of this project was altered in order to try and understand the source of this observed selectivity, and rationally improve upon it. Target compounds were designed to probe which amino acid residue differences were responsible for the selectivity, and from this a hypothesis was generated. The end result was a lead compound with three stereocentres around a piperidine framework, sub-micromolar potency, and over twice the level of BD2-selectivity at BRD4 of any compounds reported to date. This compound, and the approach taken to discover it, represents an important contribution to the art and provides a basis for further investigations in this scientific field.
Date of Award11 May 2018
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde & Glaxo Smithkline (UK)
SupervisorAllan Watson (Supervisor) & William Kerr (Supervisor)

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