Discovery of Eucalyptin C, derived from the fruits of Eucalyptus globulus Labill., as a novel selective PI3Kγ inhibitor for immunosuppressive treatment

The fruits of Eucalyptus globulus Labill. are known to have a plenty of medicinal properties, such as anti-tumor, anti-inflammatory, and immunosuppressive activity. Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E. globulus were immunosuppressive active constituents, especially Eucalyptin C (EuC). Phosphoinositide 3-kinases-gamma (PI3K gamma) plays a pivotal role in T cell mediated excessive immune responses. In this study, EuC was first discovered to be a novel selective PI3K gamma inhibitor with an IC50 value of 0.9 mu mol.L-1 and selectivity over 40-fold towards the other PI3K isoforms. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay showed that EuC bound to PI3K gamma. Furthermore, EuC suppressed the downstream of PI3K gamma to induce the apoptosis and inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice. This work highlights the role of the fruits of E. globulus as a source of bioactive plant with immunosuppressive activity.