PI3Kγ
PI3Kγ is an emerging target for inflammatory diseases. PI3Kγ is a lipid kinase, which represents one of four isoforms of class I phosphatidylinositol-3-Kinases. PI3Kγ acts downstream of G-Protein Coupled Receptors and is a key mediator of directed movement of immune cells towards chemoattractants. It is also involved in other immune responses, such as the respiratory burst of neutrophils, mast cell degranulation and T-cell development. Inhibition of the lipid kinase activity of PI3Kγ has been shown by several laboratories, both genetically and by inhibition with tool compounds, to have a beneficial effect in models of disease, like rheumatoid arthritis and Lupus erythematosus.
We have developed a » Kinobeads™ based assay for PI3Kγ, which utilizes the kinase in its physiological state, with the right modifications and protein partners present. Utilizing this assay in a screen of our compound library, we have identified several series which are being optimized using the Kinobeads™ assay and were subsequently developed to leads which show in vivo efficacy in appropriate models. The Kinobeads™ approach further enables us to address the selectivity of our compounds over other members of class I PI3-Kinases and also more broadly over lipid and protein kinases.
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