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

Winkler DG, Faia KL, DiNitto JP et al. - Chemistry and Biology Nov 13 20, 1364-1374

Phosphoinositide-3 kinases (PI3K) are cell signalling proteins that act as a central node for relaying signals from cell surface receptors and downstream mediators. Specifically they phosphorylate phosphatidylinositol to phosphatidylinositol-3,4,5-trisphosphate (PIP3). This acts a docking site for signalling proteins, leading to the activation of downstream effectors such as BTK. Therefore, inhibition of the PI3K-d and PI3K-? isoforms (PI3K-a and PI3K-ß demonstrated embryonic lethality in murine models) could potentially have anti-inflammatory effects by affecting both adaptive and innate immune response. This paper describes the structure and effects of IPI-145, a small molecule inhibitor of PI1K-d and PI3K-?, which has shown inhibitory effects on B and T cell proliferation, blocking neutrophil migration and basophil activation inhibition in in vivo assays. This study further explored the therapeutic value of dual inhibition of PI3K-d and PI3K-?, with IPI-145 showing potent therapeutic activity in collagen-induced arthritis (CIA), ovalbumin-induced asthma and systemic lupus erythematosus, and also showed significant efficacy in small animal models of inflammatory and autoimmune diseases. The authors that conclude that these results merit clinical exploration in inflammatory and autoimmune diseases as well as hematologic malignancies.

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Upload date: January 2014

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