title: Targeting phosphoinositide 3-kinase δ for allergic asthma.
abstract: Chronic inflammation in the lung has long been linked to the pathogenesis of asthma. Central to this airway inflammation is a T-cell response to allergens, with Th2 cytokines driving the differentiation, survival and function of the major inflammatory cells involved in the allergic cascade. PI3Kδ (phosphoinositide 3-kinase δ) is a lipid kinase, expressed predominantly in leucocytes, where it plays a critical role in immune receptor signalling. A selective PI3Kδ inhibitor is predicted to block T-cell activation in the lung, reducing the production of pro-inflammatory Th2 cytokines. PI3Kδ is also involved in B-cell and mast cell activation. Therefore the inhibition of PI3Kδ should dampen down the inflammatory cascade involved in the asthmatic response through a wide breadth of pharmacology. Current anti-inflammatory therapies, which are based on corticosteroids, are effective in controlling inflammation in mild asthmatics, but moderate/severe asthmatic patients remain poorly controlled, experiencing recurrent exacerbations. Corticosteroids have no effect on mast cell degranulation and do not act directly on B-cells, so, overall, a PI3Kδ inhibitor has the potential to deliver improvements in onset of action, efficacy and reduced exacerbations in moderate/severe asthmatics. Additionally, PI3Kδ inhibition is expected to block effects of Th17 cells, which are increasingly implicated in steroid-insensitive asthma.
authors.affiliation: Biological Reagents and Assay Development, Platform Technology and Science, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Rowan
authors.forename: Janet L
authors.initials: JL
authors.lastname: Smith
authors.forename: Karen
authors.initials: K
authors.lastname: Affleck
authors.forename: Augustin
authors.initials: A
authors.lastname: Amour
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors