Development of chemical probes for non-BET bromodomains

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2016
Thesis identifier
  • T15972
Qualification Level
Qualification Name
Department, School or Faculty
  • This thesis describes the development and discovery of chemical probe molecules for non-BET bromodomains. Studies have demonstrated that inhibitors of the BET family of bromodomains show profound anti-cancer and anti-inflammatory properties, with several molecules entering clinical trials. However, the BET family represents just 8 of the 56 human bromodomains identified, leaving the majority of this intriguing target class yet to be investigated. Chemical probes are an essential component of the biological tool set required to delineate the function of bromodomains for both target validation and invalidation. Therefore, this thesis describes the studies towards the identification of chemical probes for non-BET bromodomains to facilitate elucidation of their biological roles. Firstly, the development of I-BRD9, the first selective cellular probe for Bromodomain Containing Protein 9 (Brd9) is presented. I-BRD9 was identified through iterative medicinal chemistry, starting from a potent but unselective amide. Structure-based design was used to guide modifications to the scaffold to deliver excellent activity (Brd9 pKd: 8.7) and greater than 70-fold selectivity for Brd9 over every other bromodomain tested. I-BRD9 shows good selectivity over 49 pharmacologically relevant targets, and evidence of Brd9 cellular target engagement. The compound is now freely available to the scientific community through the Structural Genomics Consortium or for purchase via commercial suppliers. Therefore, the biological effect of Brd9 bromodomain inhibition can be investigated for the first time. Secondly, focus was placed on the development of a chemical probe for Transcription initiation factor TFIID subunit 1 (TAF1). Starting from a hit identified in a cross-screen, work was carried out to optimise the activity, selectivity and physicochemical properties of the chemotype. A compound with excellent TAF1 BD2 activity (pIC50: 7.2) and ≥80-fold selectivity over every bromodomain tested was identified. However, the compound shows poor permeability, therefore, further work to optimise the physico-chemical properties of the template is required.
Advisor / supervisor
  • Humphreys, Philip
  • Tomkinson, Nicholas
Resource Type
  • This thesis was previously held under moratorium between March 2016 and 18 June 2021.
  • The confidentiality statement on each page of this thesis DOES NOT apply
Date Created
  • 2016