Discovery of Dual Inhibitors of the Immune Cell PI3Ks p110δ and p110γ: a Prototype for New Anti-inflammatory Drugs

PI3K delta and PI3K gamma regulate immune cell signaling, while the related PI3K alpha and PI3K beta regulate cell survival and metabolism. Selective inhibitors of PI3K delta/gamma represent a potential class of anti-inflammatory agents lacking the anti proliferative effects associated with PI3K alpha/beta inhibition. Here we report the discovery of PI3K alpha/beta inhibitors that display up to 1000-fold selectivity over PI3K alpha/beta and evaluate these compounds in a high-content inflammation assay using mixtures of primary human cells. We find selective inhibition of only PI3K delta is weakly anti-inflammatory, but PI3K delta/gamma inhibitors show superior inflammatory marker suppression through suppression of lipopolysaccharide-induced TNF alpha production and T cell activation. Moreover, PI3K delta/gamma 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.