Synthesis and optimisation of novel molecules to probe epigenetic mechanisms with applications in the treatment of inflammatory disorders

  • Hawa Diallo

Student thesis: Doctoral Thesis


Jumonji (Jmj) histone demethylases are Fe(II) and α-oxoglutarate dependent oxygenases that constitute essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues found in histones, in a methylation-state and sequence-specific context. This report is the first account of a structure-guided small molecule and chemoproteomics approach to elucidate the functional role of JmjD3. In an effort to discover suitable chemotypes for further optimisation against JmjD3, a focused screen and high throughput screen were performed. These screens identified a number of hits, of which the initial investigations of three are discussed in this report. The demonstration of SAR for the pyridyl-pyrimidine series, and confirmation of binding in the JmjD3 active site by X-ray crystallography, led to this template being selected for further optimisation by improving the interaction with a key residue in the active site. The optimisation of this series enabled the identification of the first small molecule inhibitor selective for JmjD3. This small molecule inhibitor was shown to successfully engage the endogenous JmjD3 using a chemproteomics approach and reduce lipopolysaccharide-induced pro-inflammatory cytokine production in human primary macrophages. This report provides encouragement for designing small molecule inhibitors to enable selective pharmacological intervention across the Jmj family.
Date of Award13 Oct 2014
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsEPSRC (Engineering and Physical Sciences Research Council) & University of Strathclyde

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