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

Abstract

Abstract Inhibitors of Phosphatidylinositol-3-Kinase (PI3K) are of significant interest due to their ability to target an intracellular pathway, which regulates cell proliferation, growth, and migration. Mutations in PI3K can lead to an upregulation of the pathway, resulting in tumorigenesis, autoimmunity, and leukemia in the immune system, while a nonfunctional PI3K can result in immunodeficiency. Wortmannin, a known and potent PI3K inhibitor, possesses many unfavorable characteristics as a chemotherapeutic and immunotherapy drug such as its insolubility in neutral buffers, limited supply, and high toxicity in vivo, which have prevented its clinical application. The small molecule inhibitor Hibiscone C, synthesized from the readily available precursors acetone and isobutylaldehyde, shares the same structural chemistry at the binding site as Wortmannin, suggesting that it shares similar biological activity. 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 due to the presence of the furanosteroid ring, to which PI3K covalently binds in each molecule. As predicted by the lack of functional groups in Hibisconce C that are present in Wortmannin, Hibiscone C was found to be less potent of an inhibitor. Despite this reduced inhibitory potency, Hibiscone C serves as a minimalist structure with which to study the requirements for PI3K binding affinity and inhibition. This reduced structure can be manipulated in order to synthesize derivatives that can maximize potency, specificity, and solubility.