Analysis of Hibiscone C derivatives in the inhibition of the Phosphatidylinositol-3-Kinase (PI3K) Pathway in Activated T-Cells 2124

Abstract Description The phosphatidylinositol-3-kinase (PI3K) pathway is involved in the regulation of proliferation and growth in many cells, including T cells. Gain-of-function mutations in the pathway can cause abnormal cell proliferation and have been implicated in several leukemias. Wortmannin is a furanosesquiterpenoid that has been shown to be effective in inhibiting the PI3K pathway in activated T-cells. However, Wortmannin is unstable, difficult to synthesize, and toxic in vivo limiting its use as a chemotherapeutic. 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. Through the analysis of phosphorylation of the downstream effector molecule Akt in activated T cells, we previously demonstrated that Hibiscone C can irreversibly inhibit PI3K activity albeit less effectively than Wortmannin. These results led us to test a variety of Hibiscone C derivatives to assess how modification affected the potency of the molecule. Hibiscone BD and acetylated Hibiscone B effectively inhibited the PI3K pathway, whereas Hibiscone B exhibited similar potency to Hibiscone C. These studies demonstrate that alterations of the furan ring can be made to the molecule without compromising potency and shines light on how these furanosesquiterpenoids inhibit PI3K activity, which may ultimately lead to the discovery of one that can be used as a chemotherapeutic. Funding Sources NSF SC INBRE (NIH) SC Space Grant (NASA) Furman University Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)