Discovery of dual inhibitors of the immune cell PI3Ks p110δ and p110γ: a prototype for new anti-inflammatory drugs.

Authors: Williams O, Houseman BT, Kunkel EJ, Aizenstein B, Hoffman R, Knight ZA, Shokat KM.
Publisher/Year: Chemistry & Biology. 2010;17(2):123–134.
Pub Med ID/Journal ID: PMID: 20189103


PI3Kδ and PI3Kγ regulate immune cell signaling, while the related PI3Kα and PI3Kβ regulate cell survival and metabolism. Selective inhibitors of PI3Kδ/γ represent a potential class of anti-inflammatory agents lacking the antiproliferative effects associated with PI3Kα/β inhibition. Here we report the discovery of PI3Kδ/γ inhibitors that display up to 1000-fold selectivity over PI3Kα/β and evaluate these compounds in a high-content inflammation assay using mixtures of primary human cells. We find selective inhibition of only PI3Kδ is weakly anti-inflammatory, but PI3Kδ/γ inhibitors show superior inflammatory marker suppression through suppression of lipopolysaccharide-induced TNFα production and T cell activation. Moreover, PI3Kδ/γ inhibition yields an anti-inflammatory signature distinct from pan-PI3K inhibition and known anti-inflammatory drugs, yet bears striking similarities to glucocorticoid receptor agonists. These results highlight the potential of selectively designing drugs that target kinases with shared biological function.