The Inhibition of Phosphatidylinositol-3-Kinase in activated T-cells by Hibiscone C derivatives

PAC Gym

The phosphatidylinositol-3-kinase (PI3K) pathway is of significant interest due to its ability to regulate cell proliferation, growth, and migration in numerous contexts including in T cells. Furthermore, gain-of-function mutations in PI3K can lead to an upregulation of the pathway, resulting in tumorigenesis, autoimmunity, and leukemia. Specific furanosesquiterpenoids, such as wortmannin, have been known to inhibit the PI3K pathway in T cells. However, wortmannin has unfavorable characteristics as a chemotherapeutic or immunomodulatory drug due to its insolubility in neutral buffers, instability, and high toxicity in vivo. Hibiscone C, another furanosesquiterpenoid, lacks many of the functional groups as wortmannin, but contains the critical diacyl furan ring that is vital for interacting with the ATP binding pocket of PI3K. Via analysis of phosphorylation of the downstream effector molecule Akt in activated T cells, we demonstrate that hibiscone C also can irreversibly inhibit PI3K activity, however not as effectively as wortmannin. These results led us to test other derivatives of hibiscone C, to see if modifications to the molecules structure would affect potency of the molecule. Reduction of either of the carbonyl groups of the furan ring show reduced inhibitory activity compared to hibiscone C. Reduction of both carbonyls also shows reduced potency but in addition abolishes the irreversibility of the inhibition. Modifications that increase electrophilicity show similar inhibitory activity compared to hibiscone C. These data suggest that while these carbonyls are important for maximal binding to PI3K, they are not absolutely required to achieve inhibition, while the addition of electron withdrawing groups could optimize PI3K inhibition. These findings provide avenues for further manipulations of hibiscone C functional groups to maximize efficacy of the molecule.