PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models

Chem Biol. 2013 Nov 21;20(11):1364-74. doi: 10.1016/j.chembiol.2013.09.017.

David G Winkler ¹, Kerrie L Faia, Jonathan P DiNitto, Janid A Ali, Kerry F White, Erin E Brophy, Melissa M Pink, Jennifer L Proctor, Jennifer Lussier, Christian M Martin, Jennifer G Hoyt, Bonnie Tillotson, Erin L Murphy, Alice R Lim, Brian D Thomas, John R Macdougall, Pingda Ren, Yi Liu, Lian-Sheng Li, Katti A Jessen, Christian C Fritz, Joi L Dunbar, James R Porter, Christian Rommel, Vito J Palombella, Paul S Changelian, Jeffery L Kutok

Affiliations

Affiliation

1 Infinity Pharmaceuticals, Inc., Cambridge, MA 02139, USA.

PMID: 24211136 DOI: 10.1016/j.chembiol.2013.09.017

Abstract

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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