Discovery of Dual Inhibitors of the Immune Cell PI3Ks p110δ and p110γ: a Prototype for New Anti-inflammatory Drugs
| Autor: | Brian Aizenstein, Eric J. Kunkel, Kevan M. Shokat, Benjamin T. Houseman, Zachary A. Knight, Olusegun Williams, Randy Hoffman |
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| Rok vydání: | 2010 |
| Předmět: |
Lipopolysaccharides
Cell signaling Class I Phosphatidylinositol 3-Kinases T cell Clinical Biochemistry Cell Anti-Inflammatory Agents Biology Pharmacology Lymphocyte Activation Biochemistry Article Phosphatidylinositol 3-Kinases Immune system Drug Discovery medicine Class Ib Phosphatidylinositol 3-Kinase Humans Enzyme Inhibitors Molecular Biology Cells Cultured Phosphoinositide-3 Kinase Inhibitors Quinazolinones Tumor Necrosis Factor-alpha Kinase Drug discovery General Medicine Isoenzymes CHEMBIO medicine.anatomical_structure SIGNALING P110δ Molecular Medicine Signal transduction Signal Transduction |
| Zdroj: | Chemistry & Biology. 17:123-134 |
| ISSN: | 1074-5521 |
| DOI: | 10.1016/j.chembiol.2010.01.010 |
| Popis: | PI3Kdelta and PI3Kgamma regulate immune cell signaling, while the related PI3Kalpha and PI3Kbeta regulate cell survival and metabolism. Selective inhibitors of PI3Kdelta/gamma represent a potential class of anti-inflammatory agents lacking the antiproliferative effects associated with PI3Kalpha/beta inhibition. Here we report the discovery of PI3Kdelta/gamma inhibitors that display up to 1000-fold selectivity over PI3Kalpha/beta and evaluate these compounds in a high-content inflammation assay using mixtures of primary human cells. We find selective inhibition of only PI3Kdelta is weakly anti-inflammatory, but PI3Kdelta/gamma inhibitors show superior inflammatory marker suppression through suppression of lipopolysaccharide-induced TNFalpha production and T cell activation. Moreover, PI3Kdelta/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. |
| Databáze: | OpenAIRE |
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