Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis
Copyright policy )Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis
Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.
- University of Turin Italy
- Instytut Farmaceutyczny Poland
- University of Basel Switzerland
- University of Turin Italy
Mice, Knockout, Mice, Inbred BALB C, Mice, Inbred C3H, Binding Sites, Molecular Structure, Molecular Sequence Data, Dioxoles, Peritonitis, Arthritis, Rheumatoid, Isoenzymes, Chemotaxis, Leukocyte, Disease Models, Animal, Mice, Phosphatidylinositol 3-Kinases, Mice, Inbred DBA, Quinoxalines, PI3K; inflammation; arthritis; pharmacological inhibitors, Animals, Enzyme Inhibitors, Phosphoinositide-3 Kinase Inhibitors, Signal Transduction
Mice, Knockout, Mice, Inbred BALB C, Mice, Inbred C3H, Binding Sites, Molecular Structure, Molecular Sequence Data, Dioxoles, Peritonitis, Arthritis, Rheumatoid, Isoenzymes, Chemotaxis, Leukocyte, Disease Models, Animal, Mice, Phosphatidylinositol 3-Kinases, Mice, Inbred DBA, Quinoxalines, PI3K; inflammation; arthritis; pharmacological inhibitors, Animals, Enzyme Inhibitors, Phosphoinositide-3 Kinase Inhibitors, Signal Transduction
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