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 same diacyl furan ring that is critical 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 molecule’s structure would affect potency of the molecule.
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