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

The fruits of Eucalyptus globulus Labill. are known to have a plethora of medicinal properties, such as anti-cancer, anti-inflammation, and immunosuppressive activity. Our previous study found that the phloroglucinol-sesquiterpene adducts in the fruits of E. globulus were its immunosuppressive active constituents, especially Eucalyptin C (EuC). Phosphoinositide 3-kinases-γ (PI3Kγ) plays a pivotal role in T cell mediated excessive immune responses. In this study, EuC was firstly discovered to be a novel selective PI3Kγ inhibitor with IC50 value of 0.9 μM and selectivity over 40-fold toward other PI3K isoforms. Molecular docking, molecular dynamics simulation, and cellular thermal shift assay showed that EuC bound to PI3Kγ. Furthermore, EuC could suppress the downstream of PI3Kγ to induce the apoptosis and to inhibit the activation of primary spleen cells derived from allergic contact dermatitis mice. This work highlights the relevance of the fruits of E. globulus as a source of bioactive plant with immunosuppressive activity.