Buzrieda, Anas
(2021)
Discovery of highly potent and selective phosphatidylinositol 3-kinase-δ inhibitors for the treatment of blood cancers and autoimmune diseases.
PhD thesis, University of Nottingham.
Abstract
Phosphatidylinositol-3-kinase (PI3K) are a group of the lipid kinases superfamily, that play a crucial role in signalling pathways involved in the regulation of numerous cellular processes such as survival, growth, proliferation and differentiation. PI3K δ belongs to the class-IA subset of PI3Ks and is mainly present in leukocytes, where it regulates the development and function of adaptive immune cells (the B and T lymphocytes). However, PI3K δ dysregulation is implicated in human diseases, including blood cancers such as leukaemia and autoimmune diseases such as rheumatoid arthritis. The selective inhibition of PI3K δ may therefore provide an exciting therapeutic opportunity to treat different types of haematological malignancies and autoimmune disorders.
Idelalisib (8) is the only selective PI3K δ inhibitor approved by the Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukaemia, small lymphocytic lymphoma and follicular lymphoma. However when dosed, idelalisib (8) has been shown to have several side effects such as chronic diarrhoea, colitis and hepatotoxicity, which often lead to the discontinuation of treatment. Therefore, this medicinal chemistry research was undertaken with the aim to discover alternative PI3K δ inhibitors that can display comparable or greater potency and selectivity than idelalisib (8), but without adverse effects.
The first chapter describes how the non-selective PI3K inhibitor pictilisib (4) was used as the starting point for the design and synthesis of novel, flat-shaped PI3K δ selective inhibitors containing the thienopyrimidine scaffold. Herein, structural modifications were performed on pictilisib (4) based on its key reported interactions seen in the ligand co-crystal structure with PI3K δ.
The aim of the research presented in this chapter was to optimize the interactions in the conserved affinity pocket and to occupy the unexploited tryptophan shelf, the space between Trp760 and Thr750, that is exclusively
found in the PI3K δ isoform and not in the other three isoforms (α, β and Ɣ).This optimization strategy led to the synthesis of 38 thienopyrimidine derivatives as new PI3K δ inhibitors. Among them, indole analogue 48,
bearing a fluoropiperidine group was identified as the best compound, due to its combination of low nanomolar potency for PI3K δ inhibition and excellent selectivity for PI3K δ over the other isoforms. In addition, it possesses favourable predicted physicochemical properties for oral administration.
Based on the docking studies from ligand crystal structure studies from other research groups, it was hypothesized that aliphatic heterocycles such as fluoropiperidine may form a favourable C-H/pi interaction with the tryptophan shelf, which may explain the improved PI3K δ potency and selectivity of compound 48. On the other hand, occupancy of the affinity pocket by the indole ring of compound 48 may aid in increasing the PI3K δ selectivity through the formation of a distal hydrogen bond network that can be accommodated only in PI3K δ.
Chapter 3, 4 and 5 focused on propeller-shaped PI3K δ inhibitors. The crystal structure of the FDA-approved idelalisib (8) bound to PI3K δ showed that the affinity pocket is not occupied in this class of inhibitor. Therefore, the goal of the work in chapters 2 and 3 was to extend the structure 8 (IC50 = 11 nM) into the unoccupied affinity pocket so as to further improve the PI3K δ potency. However, this structure-based approach proved unsuccessful with all 18 extended idelalisib analogues exhibiting weak or no activity against PI3K δ,suggesting that chemical modification of the core structure of 8 was needed. Consequently, chapter 5 reports, bioisosteric replacement of the purine group of idelalisib (8) with a 4-aminopyrimidine ring, followed by addition of a new affinity pocket-binding substituent at the C-5 position of this ring. The resulting 11 aminopyrimidine analogues displayed excellent inhibitory activity against PI3K δ at a single concentration of 500 nM. For example, the cyclohexyl analogue 218, showed 87.7% of PI3K δ inhibitory activity. Unfortunately, full determination of the IC50 values of the 4-aminopyrimidine derivatives against PI3K δ has been delayed due to the COVID-19 pandemic. However, these results will be obtained from our collaborator in Monash, and if successful will hopefully form the basis of a publication.
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