Biological Activity
pki : 9.9gsk2269557 is an inhibitor of pi3kδ.phosphoinositide 3-kinase delta (pi3kδ), a lipid kinase belonging to the class 1 pi3k family, catalyzes the phosphorylation of phosphatidylinositol-4,5-bisphosphate to produce the critical signalling molecule phosphatidylinositol-3,4,5-triphosphate and then triggers various downstream biological events that ultimately regulate cell proliferation, growth, differentiation, chemotaxis and survival.
in vitro
in the screening study, gsk2269557 met the original potency goal in the pbmc assay (pic50 >9) and showed exquisite selectivity against the pi3k isoforms in a modified htrf assay. moreover, gsk2269557 could induce concentration-dependent increases in qt interval and tpe at 0.3 and 1 μm and an increase in qrs at 1 μm, however, no treatment-related tdp arrhythmias were seen [1].
in vivo
in a disease relevant brown norway rat acute ova model of th2 driven lung inflammation, gsk2269557 was found to be albe to protect against eosinophil recruitment with an ed50 of 67 μg/kg. the activity of gsk2269557 was also assessed using other endpoints, leukocyte recruitment to the lung (neutrophils, macrophages, cd4 and cd8 t-lymphocytes at 48 hours) and th2 cytokines such as il-13. it was found that gsk2269557 could reduce recruitment of all leukocyte subpopulations and il-13 in the lungs in a dose-dependent manner [1].
References
[1] down, k. ,amour, a.,baldwin, i.r., et al. optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease. j. med. chem. 58(18), 7381-7399 (2015).
[2] robert wilson, anthony cahn, amanda deans, iain mcsherry, curtis rambaran, ana sousa, darren wilbraham. safety, tolerability and pharmacokinetics (pk) of single and repeat nebulised doses of a novel phosphoinositide 3-kinase δ inhibitor (pi3kδ), gsk2269557, administered to healthy male subjects in a phase i study. european respiratory journal 2013 42: p729.
