Novel PI3Kδ inhibitors for the treatment of inflammatory diseases

Previously held under moratorium in Chemistry Department (GSK) from 2/2/16 to 24/08/21The confidentiality statement on each page of this thesis DOES NOT applyThis thesis explores the design, synthesis and biological testing of a range of compounds targeting the selective inhibition of phosphoinositide-3-kinase δ (PI3K). The initial aim of this work was to investigate novel replacements for a 2-methoxypyridine moiety, a privileged structure which binds to PI3K in the back pocket region of the protein. Utilising computer aided design, novel groups that bind in the back pocket region were identified to bind to the protein through a conserved water molecule or displace it altogether. From this, a lead compound was selected to further optimise to identify compounds with increased selectivity and potency for PI3Kδ. Investigation of the amide substituent led to an increased understanding of the PI3Kδ back pocket region (e.g. 105), through the design and synthesis of compounds that open up a region unreported in the literature, whilst enhancing selectivity for PI3Kδ against the other class I PI3K isoforms. Investigation of the sulfonamide substituent led to the identification of potent and selective compounds (e.g. 240) which accessed an area known to give potency and selectivity from a novel vector unreported in the literature. Although the profiles of the molecules are not optimal, further work in this area could lead to more drug-like compounds with more favourable cellular potency and increased microsomal stability.Beyond the work presented in chapters 4 and 5, two further chapters are reported in which two diversified approaches are taken. In chapter 6, utilising a selection of novel back pocket groups discovered in chapter 4, the sulfonamide functionality is reversed in order to ascertain how this would change the binding mode and potency of the compounds. Initial results were disappointing, however after modification to the structure and crucial co-crystallographic data, compounds of high potency and efficiency have been synthesised (e.g. 284) which could lead to a promising novel chemical series. Finally, in chapter 7, initially using a fragment based approach with a compound identified in chapter 4 along with recently reported literature compounds, a combination of computational chemistry and modelling has led to an interesting series of compounds that open an induced pocket. The focus of chapter 7 was to gain potent and selective compounds through the induced pocket, an area of the protein that has proven difficult to access through compounds without a structure similar to Idelalisib, the only marketed PI3Kδ inhibitor. The chapter ends on the establishment of two novel chemical series to be further investigated (e.g. 306 and 328).This thesis explores the design, synthesis and biological testing of a range of compounds targeting the selective inhibition of phosphoinositide-3-kinase δ (PI3K). The initial aim of this work was to investigate novel replacements for a 2-methoxypyridine moiety, a privileged structure which binds to PI3K in the back pocket region of the protein. Utilising computer aided design, novel groups that bind in the back pocket region were identified to bind to the protein through a conserved water molecule or displace it altogether. From this, a lead compound was selected to further optimise to identify compounds with increased selectivity and potency for PI3Kδ. Investigation of the amide substituent led to an increased understanding of the PI3Kδ back pocket region (e.g. 105), through the design and synthesis of compounds that open up a region unreported in the literature, whilst enhancing selectivity for PI3Kδ against the other class I PI3K isoforms. Investigation of the sulfonamide substituent led to the identification of potent and selective compounds (e.g. 240) which accessed an area known to give potency and selectivity from a novel vector unreported in the literature. Although the profiles of the molecules are not optimal, further work in this area could lead to more drug-like compounds with more favourable cellular potency and increased microsomal stability.Beyond the work presented in chapters 4 and 5, two further chapters are reported in which two diversified approaches are taken. In chapter 6, utilising a selection of novel back pocket groups discovered in chapter 4, the sulfonamide functionality is reversed in order to ascertain how this would change the binding mode and potency of the compounds. Initial results were disappointing, however after modification to the structure and crucial co-crystallographic data, compounds of high potency and efficiency have been synthesised (e.g. 284) which could lead to a promising novel chemical series. Finally, in chapter 7, initially using a fragment based approach with a compound identified in chapter 4 along with recently reported literature compounds, a combination of computational chemistry and modelling has led to an interesting series of compounds that open an induced pocket. The focus of chapter 7 was to gain potent and selective compounds through the induced pocket, an area of the protein that has proven difficult to access through compounds without a structure similar to Idelalisib, the only marketed PI3Kδ inhibitor. The chapter ends on the establishment of two novel chemical series to be further investigated (e.g. 306 and 328)