Drugging the Phosphoinositide 3-Kinase (PI3K) and Phosphatidylinositol 4-Kinase (PI4K) Family of Enzymes for Treatment o
The lipid kinases that generate the lipid signalling phosphoinositides have been established as fundamental signalling enzymes that control numerous aspects of how cells respond to their extracellular environment. In addition, they play critical roles in
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Drugging the Phosphoinositide 3-Kinase (PI3K) and Phosphatidylinositol 4-Kinase (PI4K) Family of Enzymes for Treatment of Cancer, Immune Disorders, and Viral/Parasitic Infections Jacob A. McPhail and John E. Burke
Abstract
The lipid kinases that generate the lipid signalling phosphoinositides have been established as fundamental signalling enzymes that control numerous aspects of how cells respond to their extracellular environment. In addition, they play critical roles in regulating membrane trafficking and lipid transport within the cell. The class I phosphoinositide kinases which generate the critical lipid signal PIP3 are hyperactivated in numerous human pathologies including cancer, overgrowth syndromes, and primary immunodeficiencies. The type III phosphatidylinositol 4-kinase beta isoform (PI4KB), which are evolutionarily similar to the class I PI3Ks, have been found to be essential host factors mediating the replication of numerous devastating pathogenic viruses. Finally, targeting the parasite variant of PI4KB has been established as one of the most promising strategies for the development of anti-malarial and anticryptosporidium strategies. Therefore, the development of targeted isoform selective J. A. McPhail · J. E. Burke (*) Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada e-mail: [email protected]
inhibitors for these enzymes are of paramount importance. The first generation of PI3K inhibitors have recently been clinically approved for a number of different cancers, highlighting their therapeutic value. This review will examine the history of the class I PI3Ks, and the type III PI4Ks, their relevance to human disease, and the structural basis for their regulation and inhibition by potent and selective inhibitors. Keywords
Phosphoinositides · Phosphatidylinositol · PI3K · p110 · p85 · PIK3CA · PIK3R1 · PI4K · PI4KB · PI4KA · Oncogenes · Cancer · Malaria · Cryptosporidiosis · Enteroviruses
9.1
Phosphoinositide Kinases and Their Role in Signalling/ Human Disease
9.1.1 Phosphoinositides Phosphoinositides are essential membrane signalling molecules that regulate a multitude of cellular processes, from membrane identity
© Springer Nature Switzerland AG 2020 Y. Kihara (ed.), Druggable Lipid Signaling Pathways, Advances in Experimental Medicine and Biology 1274, https://doi.org/10.1007/978-3-030-50621-6_9
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and compartmentalization to growth and cell division. While they represent a small percentage of total cellular lipid composition, their correct spatiotemporal location in a cell is an essential mechanism maintaining organelle identify and membrane trafficking [1, 2]. All phosphoinositides are generated from phosphatidylinositol (PI), and the inositol headgroup can be phosphorylated at the hydroxyls present at the D3, D4 and D5 positions, generating a total of seven different phosphoinositides: phosphatidylinositol 3-phosphate (PI3P), phosphatidylinositol 4- phosphate (PI4P), phosphatidylinositol 5- phosphate (PI5P), phosphatidylinositol 3,4-b
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