Background:

pKi : 9.9

GSK2269557 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].

Clinical trial: GSK2269557 was investigated in a double blind and placebo controlled trial in healthy males and smokers. It was found that GSK2269557 was well tolerated in healthy males. There was a low incidence of AE’s and the plasma PK was well defined confirming high levels of drug within the lung compared to plasma [2].

参考文献:
[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.