Thesis

Synthesis and biological evaluation of novel small molecule bromodomain inhibitors

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Awarding institution
  • University of Strathclyde
Date of award
  • 2019
Thesis identifier
  • T17009
Person Identifier (Local)
  • 201691526
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Epigenetics is the study of changes in gene expression without changing the primary DNA sequence. Bromodomain-containing proteins are responsible for recognising acetylated residues on histone tails, recruiting transcriptional machinery and thus facilitating gene transcription. Small molecule bromodomain inhibitors prevent this recognition, thus downregulating the transcription of pro-inflammatory cytokines which could have therapeutic effects in immuno-inflammatory diseases such as RA. A targeted approach, in which a drug is delivered selectively to target cell types associated with the disease, could minimise off-target toxicity and improve a therapeutic index. This thesis focuses on the development of an esterase sensitive motif (ESM) targeting strategy, which is selectively hydrolysed by the enzyme human carboxyesterase 1 (CES-1) to produce the biologically-active acid. Outside of the liver, this enzyme’s expression profile is limited to the mononuclear monocyte and macrophage lineages, therefore providing the opportunity to treat immuno-inflammation diseases. The investigation of two structurally differentiated series is described within this thesis. The starting point compound in the first series, in which the ESM is directed over a lipophilic groove formed by a tryptophan, proline and phenylalanine (termed the WPF shelf) suffered from high in vitro clearance (IVC) and lipophilicity. Replacement of the phenyl ring, which interacts with the WPF shelf, with five-membered heterocyclic rings was shown to be suboptimal resulting in reduced potency and poor metabolic stability (Figure 0.1). However, substitution of the six-membered ring and increasing the steric hindrance of the pyridyl core resulted in compounds with low microsomal and hepatocyte clearance (Figure 0.1). A lead molecule was identified from this series with improved physicochemical properties, and desirable potency and metabolic stability. The compound showed high selectivity for the BET family over non-BET bromodomain-containing proteins and off-targets and were shown to be substrates for CES-1. [see Figure 0.1 in thesis] The second part of this thesis focusses on the optimisation of a second structurally differentiated series with an alternative warhead, in which the ESM is directed through the ZA channel. Initial candidates showed an underlying issue with IVC. A range of substituents which acted as the shelf group were investigated. Employing the best shelf groups for IVC and replacing the phenyl ring with a pyridine or a diazine improved metabolic stability and resulted in compounds with desirable IVC profiles (Figure 0.2). Two lead molecules were identified from this series, both of which demonstrated high cellular activity and metabolic stability. They were selective for the BET family and were shown not to inhibit CYP3A4 in a time dependent manner, a common observed liability in this series. [see Figure 0.2 in thesis] Overall, work outlined in this report has taken molecules with high IVC and lipophilicity and optimised them into molecules with excellent potency, as well as desirable HLM and hepatocyte IVC and lipophilicity. Three molecules across both series were progressed into late stage cynomolgus monkey PK studies and were selected as the lead molecules for the series. Although the compounds were not progressed beyond the PK studies, they were key compounds for exemplifying that reducing cynomolgus monkey hepatocyte clearance, whilst maintaining a low lipophilicity and desirable metabolic stability, increased the oral bioavailability within cynomolgus monkeys.
Advisor / supervisor
  • Burley, Glenn
  • Liwicki, Gemma
Resource Type
Note
  • The confidentiality statement on each page of this thesis DOES NOT apply.
  • Previously held under moratorium in Chemistry department (GSK) from 3rd June 2019 until 7th June 2024
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