Development of novel modulators of protein-protein interactions associated with cancer
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An understanding of the underlying mechanisms by which proteins engage and communicate within the complex cellular environment is critical to the elucidation of the molecular basis of disease states and the development of safer, more efficacious drug therapies. Diverse cellular functions, including replication, transcription, cell growth and intracellular signal transduction, are governed by extensive networks of protein-protein interactions (PPIs). Disruption of the finely-tuned cellular networks due to the formation of aberrant or unregulated PPIs is implicated in the development and progression of cancer. As a result, over the last decade, PPI modulation has developed as an attractive molecular target for novel cancer therapies and as a powerful research tool in chemical biology to provide insight into the cellular transformations involved in carcinogenesis. Chapter 1 provides a review of the physiological importance of PPIs and the role they play in the development and progression of cancer. A summary of the challenges associated with targeting PPIs is given, highlighting the changing perception regarding the drugabbility of PPIs and the technological and conceptual advances driving this transformation. A brief overview of the approaches used to identify PPI modulators links the reader to the appropriate chapter for further discussion and utilisation of a selection of these methods. Chapter 2 describes the application of a virtual screening approach to discover PPI modulators. In particular, the development of an in silico – in vitro screening method to identify modulators of the protein interactome of the AAA+ protein reptin. The synthesis and optimisation of two hit compounds is outlined, with a discussion of their predicted binding modes, mode of action, potential as chemical tools and lead molecules for an anti-cancer drug discovery programme. Chapter 3 highlights the potential to discover PPI modulators from Nature’s rich source of structurally complex, bioactive molecules. A synthetic approach to a sub-family of tetramic acid natural products is outlined, involving the development of a short, asymmetric synthesis of unnatural 4,4-disubstituted glutamic acid derivatives. The first total syntheses of the potent siderophore harzianic acid and the PAC3 PPI inhibitor JBIR-22 are reported. In addition, the potential role of a Diels-Alderase enzyme in the biosynthesis of JBIR-22 and the development of a chiral catalysed intramolecular Diels-Alder of an advanced JBIR-22 intermediate is investigated. Chapter 4 discusses the use of structure based design techniques in the development of PPI modulators. The process involved in the design of two series of inhibitors of PICK PDZ domain mediated interactions is outlined. This leads to the development and optimisation of synthetic routes to both series of inhibitors, including the utilisation of a strategic sp3-sp2 cross coupling reaction. Finally, preliminary biological assessment of the inhibitors is reported. Chapter 5 gives a brief overview of high-throughput screening (HTS) methods used to identify PPI modulators. The utilisation of a forward chemical genetics screen to identify the p53 activator MJ05 is described. A racemic and asymmetric route to MJ05 is developed and biochemical analysis of the two enantiomers of MJ05 is reported including the investigation of MJ05 as an adjuvant therapy for the treatment of cancer. Chapter 6 provides a general overview of the outcome of the different approaches used in this research to discover PPI modulators. Particular emphasis is placed on the development of chemical tools for the elucidation and dissection of the physiological role of protein-protein interactions and the identification of novel drug targets, in addition to the identification of lead molecules for PPI drug development programmes.
Thesis, PhD Doctor of Philosophy
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