This project aims to define the properties of two Brusatol analogs (#15 and #26) that exhibited enhanced PI3K inhibition with minimal toxicity compared to their parent compound. A comprehensive evaluation of these compounds’ ability to inhibit cell proliferation will include phenotypic and functional characterization through cell viability assays and morphological analysis. Target identification and validation will support these characterization results through structure-activity relationship modeling with thermal shift assays and molecular docking simulations. Following this, molecular and virological readouts will be used to assess target expression and Epstein Barr Virus (EBV) antigen levels. These accumulated findings will guide future functional validation experiments and mechanistic pathway dissection. Given historical challenges with PI3K inhibitors’ toxicity and lack of selectivity, this project will also examine potential combinational therapies with doxorubicin and vincristine. Overall, this project aims to refine our understanding of the interplay between PI3K inhibition and EBV positive hematologic malignancies by integrating chemical biology, virology and medicinal chemistry to inform future therapeutic development in viral oncology.