Discovery of small molecule epigenetic modulators

Thesis

Target validation is increasingly becoming a central tenet to successful execution of drug discovery campaigns. An emerging approach towards the development of novel therapies for previously untreated diseases is the development of small molecule chemical probes which can be used as early stage tools for pertinent biological questions to be explored about a molecular target within the context of disease. A number of proteins which regulate epigenetic mechanisms have been correlated with disease onset and progression. Despite disease links, there remains a paucity in the understanding by which many of these pathologically relevant proteins exert their phenotypic effect when dysregulated. The discovery of novel chemical probes will facilitate further understanding of the underlying biology of these epigenetic targets. This thesis reports on the discovery and development of chemical probes and inhibitors of epigenetic proteins. A series of synthetic medicinal chemistry efforts is described towards the multiIfaceted improvements of lead compounds by means of potency, selectivity and cell activity against their cognate targets.

In chapter 1 the associated concepts, primary literature and core principles of the subsequent chapters are comprehensively examined. In chapter 2 a report on the discovery of the first chemical probe for the bromodomains of p300/CBP Associated Factor (PCAF) and General Control Nonderepressible 5 (GCN5) proteins, previously untargeted and disease relevant protein domains is described. Following this, chapter 3 describes the development of inhibitors of the second macrodomain of polyadenosine diphosphate ribosylating protein 14 (PARP14) building on the understanding of SAR around the target and reporting the most potent ligand described to date. Chapter 4 then goes on to describe the discovery a chemical probe for the YEATS domain containing proteins ENL and Af9. Up to this date there have been no reported inhibitors or chemical probes for the YEATS domain containing proteins despite numerous links to cancers.

The final chapter 5 describes the outputs from the industrial placement period of my doctoral training during which synthetic methodology and total synthesis research at Vertex Pharmaceuticals was carried out. In this chapter the substrate scope of an additive free UVIA promoted photocyclisation of arylI enamines to spiroindolines is described. The utility of this additiveIfree complexity building reaction is demonstrated through the formal synthesis of an alkaloid natural product (±)Ihorsfiline.

Authors: Moustakim, M

• DOI: 10.5287/ora-kqgo5mnjy
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English