Journal
CHEMISTRY & BIOLOGY
Volume 20, Issue 11, Pages 1364-1374Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2013.09.017
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Phosphoinositide-3 kinase (PI3K)-delta and PI3K-gamma are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral Pl3K-delta and PI3K-gamma inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-delta and PI3K-gamma blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-delta and PI3K-gamma blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.
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