Thesis

The design and synthesis of chemical probes for non-BET bromodomains

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2019
Thesis identifier
  • T16430
Person Identifier (Local)
  • 201654328
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • This thesis describes the design and synthesis of chemical probes for non-BET bromodomains. Studies have shown that inhibition of the BET bromodomains leads to profound activity in immuno-inflammation and oncology disease settings, with several BET bromodomain inhibitors entering the clinic. The validation of this new target class has led to a surge of interest in the remaining 53 non-BET bromodomains. Whilst the majority of non-BET bromodomains have been implicated in disease pathways, the biological role they play in mediating disease states is unknown. To help delineate the function of the non-BET bromodomains in disease, and establish their potential as therapeutic targets, academia and industry have begun developing chemical probes for their preclinical target validation. A chemical probe for the TAF1/TAF1L bromodomains was designed from a naphthyridinone scaffold. Statistical analysis was used to establish a relationship between permeability and pKa and, in turn, guide the optimization of permeability on the series. The developed probe molecule shows excellent potency (TAF1(2) pKD = 9.1), selectivity over the BET bromodomains (1000-fold) and other non-BET bromodomains where tested (≥50-fold), improved permeability (62 nm/s), and represents a novel chemotype for TAF1/TAF1L inhibitors. From here, the concept of conserved water interactions was explored in an attempt to further increase non-BET bromodomain selectivity for TAF1(2). A BRD7/9 template was then selected to explore the concept of bromodomain selectivity through conserved water interactions more extensively. A novel butyl acetylated Lys methyl mimetic motif was discovered and utilized to produce a selective BRD7/9 chemical probe with accompanying negative control. The broader applicability of the butyl motif was then demonstrated across a variety of scaffolds to enhance selectivity for BRD7/9 in a predictable manner.
Advisor / supervisor
  • Tomkinson, Nicholas
  • Humphreys, Philip
  • Liwicki, Gemma
Resource Type
Note
  • Previously held under moratorium in Chemistry department (GSK) from 17th June 2020 until 23rd November 2022.
  • The confidentiality statement on each page of this thesis DOES NOT apply
DOI
Funder
Embargo Note
  • This thesis is restricted to Strathclyde users only until 17th June 2025.

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