5-(2-2-difluorobenzo(1-3)dioxol-5-ylmethylene)thiazolidine-2-4-dione and Disease-Models--Animal

Phosphoinositide 3-kinase γ (PI3Kγ) is a shared downstream component of chemokine-mediated signaling pathways and regulates migration, proliferation and activation of inflammatory cells. PI3Kγ has been shown to play a crucial role in regulating inflammatory responses during the progression of several diseases. We investigated the potential function of PI3Kγ in mediating inflammatory reactions and the development of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We found that systemic treatment with selective PI3Kγ inhibitor AS-604850 significantly reduced the number of infiltrated leukocytes in the CNS and ameliorated the clinical symptoms of EAE mice. Treatment with this PI3Kγ inhibitor enhanced myelination and axon number in the spinal cord of EAE mice. Consistently, we demonstrated that PI3Kγ deletion in knockout mice mitigates the clinical sign of EAE compared to PI3Kγ+/+ controls. PI3Kγ deletion increased the number of axons in the lumbar spinal cord, including descending 5-HT-positive serotonergic fiber tracts. Our results indicate that PI3Kγ contributes to development of autoimmune CNS inflammation and that PI3Kγ blockade may provide a great potential for treating patients with MS.

Topics: Animals; Axons; CD3 Complex; Class Ib Phosphatidylinositol 3-Kinase; Dioxoles; Disease Models, Animal; Ectodysplasins; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Neurofilament Proteins; Peptide Fragments; Phosphoinositide-3 Kinase Inhibitors; Serotonin; Severity of Illness Index; Spinal Cord; Thiazolidinediones; Time Factors

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.

Topics: Animals; Arthritis, Rheumatoid; Binding Sites; Chemotaxis, Leukocyte; Dioxoles; Disease Models, Animal; Enzyme Inhibitors; Isoenzymes; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred DBA; Mice, Knockout; Molecular Sequence Data; Molecular Structure; Peritonitis; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Quinoxalines; Signal Transduction; Structure-Activity Relationship; Thiazolidinediones