PI3K inhibitors as potential therapeutics for autoimmune disease

Abstract

Abstract:Aberrant over-activation of the immune system can give rise to chronic and persistent self-attack, culminating in autoimmune disease. This is currently managed therapeutically using potent immunosuppression and anti-

Inhibitory Effect of Idelalisib, a Selective Phosphatidylinositol 3-Kinase δ Inhibitor, on Adipogenesis in an In Vitro Model of Graves' Orbitopathy

“…PI3K signaling has a complex role in regulation of the immune system and has been identified as a therapeutic target for autoimmune diseases. 10 In a model of rheumatoid arthritis, inflammatory cytokines induced PI3Kd mRNA in cultured synoviocytes, and the selective inhibition of PI3Kd diminished joint erosion in an animal model. 20,21 PI3Kd also has potential roles in the pathogenesis of systemic lupus erythematosus and multiple sclerosis.…”

“…20,21 PI3Kd also has potential roles in the pathogenesis of systemic lupus erythematosus and multiple sclerosis. 10 Likewise, studies have identified a role of the PI3K pathway in the pathogenesis of GO. The PI3K pathway is activated by either TSHR or IGF-1R stimulation in GO orbital fibroblasts, and its activation is correlated with hyaluronan production and adipogenesis.…”

“…8,9 Emerging evidence indicates that the PI3K-AKT pathway is involved in GO, in addition to several autoimmune diseases. 3,6,10 PI3K has important roles in T cell development, survival, proliferation, and differentiation. 11 As PI3K has complementary roles in many aspects of immune function, it is a potential target for anti-inflammatory treatments.…”

“…12,13 Moreover, PI3Kd, which is required for effective humoral and cell-mediated immune responses, recently has been investigated as a potential therapeutic target in autoimmune disorders, such as rheumatoid arthritis and systemic lupus erythematosus. 10,13 Given the fundamental role of inflammation in the pathogenesis of GO, we investigated the therapeutic effect of idelalisib, a recently developed potent and selective inhibitor of the kinase activity of PI3Kd, in an in vitro model of GO. Idelalisib is globally approved as an oral treatment for B cell hematologic malignancies.…”

Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease

“…3,4,5 PI3Kδ is highly enriched in leukocytes, making it an attractive target for the treatment of inflammatory conditions, such as asthma 6 , chronic obstructive pulmonary disease 7 (COPD) and autoimmune diseases. 8 Furthermore, both PI3Kδ knock-out and kinase dead knock-in mice are viable and have a phenotype consistent with immunological effects on B-cells, T-cells and neutrophils. 9 PI3Kγ is also a reported target in inflammatory disease 10 and mutagenic mice are again viable, however PI3Kα and β knock-out mice are embryonically lethal, indicating the importance of subtype specific inhibitors for therapeutic intervention.…”