Chemistry & Biology
Volume 20, Issue 11, 21 November 2013, Pages 1364-1374
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Article
PI3K-δ and PI3K-γ Inhibition by IPI-145 Abrogates Immune Responses and Suppresses Activity in Autoimmune and Inflammatory Disease Models

https://doi.org/10.1016/j.chembiol.2013.09.017Get rights and content
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Highlights

  • IPI-145 is a potent, oral class I PI3K inhibitor targeting PI3K-δ and PI3K-γ

  • IPI-145 inhibits adaptive and innate immune function

  • IPI-145 is orally active in therapeutic models of inflammatory and autoimmune disease

  • IPI-145 has therapeutic potential for autoimmune disease and hematopoietic cancers

Summary

Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ 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 PI3K-δ and PI3K-γ 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-δ and PI3K-γ 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-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases.

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Present address: Amgen Inc., Thousand Oaks, CA 91320, USA